Antibacterial phenolic compounds from the flowering plants of Asia and the Pacific: coming to the light

Article type: Review Article

Keywords: Angiosperms, antibiotics, Asia-Pacific, inflammation, superbugs

Authors: Mazdida Sulaiman ⚬, Layane Ebehairy, Veeranoot Nissapatorn ⚬, Mohammed Rahmatullah ⚬, Jhonnel Villegas ⚬, Helina Jean Dupa ⚬, Ricksterlie C. Verzosa, Karma G. Dolma ⚬, Muhamad Shabaz, Scholastica Lanting, Nor Azizun Rusdi ⚬, Nor Hayati Abdullah ⚬, Mohammed Khaled Bin Break ⚬, Teng Jin Khoo ⚬, Wei Wang ⚬, Christophe Wiart ⚬

Affiliations: Department of Chemistry, Faculty of Science, Universiti Malaya, Kuala Lumpur, Malaysia; School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat, Thailand; Department of Biotechnology, University of Development Alternative, Dhaka, Bangladesh; Faculty of Education and Teacher Training, Davao Oriental State University, Mati, Philippines; Faculty of Agriculture and Life Science, Davao Oriental State University, Mati, Philippines; Department of Microbiology, Sikkim Manipal University, Gangtok, India; Institute for Tropical Biology and Conservation, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia; Natural Product Division, Forest Research Institute of Malaysia, Kepong, Malaysia; Department of Pharmaceutical Chemistry, College of Pharmacy, University of Ha’il, Ha’il, Saudi Arabia; School of Pharmacy, University of Nottingham Malaysia, Semenyih, Malaysia; School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China

License: © 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. CC BY 4.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

Article links: DOI: 10.1080/13880209.2024.2407530  |  PubMed: 39392281  |  PMC: PMC11486068

Relevance: Moderate: mentioned 3+ times in text

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Introduction

The resistance of bacteria to antibiotics has increased to the point that treating nosocomial infections in intensive care units has become difficult, and in some cases even impossible. The list of bacterial strains resistant to antibiotics continues to grow. The intrinsic mechanisms of resistance in Gram-negative bacteria to antibiotics include, at least in part, an outer lipopolysaccharides coat carrying a net negative charge which halts (partially) the entry of negatively charged molecules (Denyer and Maillard ref. 2002; van den Berg ref. 2010) as well as porins preventing the penetration of lipophilic molecules (Bauer et al. ref. 1988; van den Berg ref. 2010). Bacteria keep on exchanging genes (among other things via plasmid transfer) coding for efflux pumps, such as NorA (Sun et al. ref. 2020), TetK in Staphylococcus aureus (Macêdo et al. ref. 2022), and AcrAB in Escherichia coli (Kuete et al. ref. 2010). Other resistance mechanisms acquired through gene exchange include enzymes that inactivate antibiotics (β-lactamases) (Eumkeb et al. ref. 2010; Siriwong et al. ref. 2015) and structurally altered bacterial targets (Oyedemi et al. ref. 2016).

The mode of action of antibiotics, which target a specific bacterial macromolecule or enzyme, sooner or later leads to the inevitable development of resistance. Some superbugs have accumulated genes of resistance to almost all known antibiotics (Willyard ref. 2017). Examples are Mycobacterium tuberculosis (clinical isolate CIBIN 99) (Uc-Cachón et al. ref. 2014), methicillin-resistant S. aureus (MRSA) SCCmec III (Asghar ref. 2014) and USA300 strains (Carrel et al. ref. 2015), Stenotrophomonas maltophilia (Gordon and Wareham ref. 2010), and vancomycin-resistant enterococcus (VRE) (Tan, Hua, et al. ref. 2020). Acinetobacter baumannii, which began as a hospital commensal bacterium, has transformed over the last decades into a bacterium resistant to almost all antibiotics (Osterburg et al. ref. 2009). In 2016, the World Health Organization (WHO) listed carbapenem-resistant A. baumannii as first on the list of bacteria posing a threat to human health (Willyard ref. 2017). In 2019, Nichols described the case of a 48-year-old man succumbing to a pan-resistant A. baumannii following a lung transplant (Nichols ref. 2019). The number of bacterial strains on the verge of becoming resistant to all antibiotics continues to increase inexorably, and among them is E. coli O157:H7 posing the risk of incurable food poisoning (Haile et al. ref. 2022).

Identifying antibacterial molecules with chemical structures completely different from those of antibiotics currently in use and capable of evading or inhibiting bacterial resistance is an urgent necessity (Chusri et al. ref. 2009). There are numerous sources of antibacterial compounds in the living world, particularly in flowering plants. Flowering plants also called Angiosperms are organized into 11 major taxa or clades distributed into three groups: (i) basal Angiosperms (protomagnoliids, magnoliids, monocots, and eudicots), (ii) core Angiosperms (core eudicots, rosids, fabids, and malvids), and (iii) upper Angiosperms (asterids, lamiids, and campanulids) (Byng et al. ref. 2009). Within each clade, plants are grouped into different orders, families, genera, and species producing secondary metabolites, one of those roles is often to fight against bacterial infections. These antibacterial natural products are either present in plants before bacterial infection (phytoanticipins) or synthesized during bacterial infection (phytoalexins) (Van Etten et al. ref. 1994). Compared to antibiotics, they do not have a single bacterial target (Yuan et al. ref. 2021). Their antibacterial activity is in vitro qualitatively evaluated using paper discs or agar wells and quantified by calculating the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). When the MBC/MIC ratio is ≤4, the compounds are bactericidal whereas a MBC/MIC ≥ 8 indicates a bacteriostatic effect (Huang et al. ref. 2021). Phytoanticipins and phytoalexins can act synergistically with antibiotics, in which case the fractional inhibitory concentration index (FICI) is <0.5 (Miklasińska-Majdanik et al. ref. 2018). These antibacterial agents belong to three major phytochemical groups: alkaloids, terpenes, and phenolic compounds.

Phenolic compounds are structurally defined by a benzene ring substituted by at least one hydroxyl group. They are organized into two categories: non-flavonoids and flavonoids, and they occupy a major role in plant defense against bacteria (Weinstein and Albersheim ref. 1983). Several observations made since the 1940s indicate that phenolic compounds can escape acquired bacterial resistance. As early as 1945, Fogg and Lodge observed that Enterobacter aerogenes could not develop resistance to phenolic compounds (Fogg and Lodge ref. 1945). More recently, Chen et al. (ref. 2018) reported the almost impossibility of S. aureus to develop resistance against a phenolic compound identified from an Asian orchid used in traditional Chinese medicine. At the same time, there is growing evidence that phenolic compounds can weaken the resistance of bacteria to antibiotics and enhance the activity of antibiotics.

The hypothesis of using phenolic compounds as a source of antibacterial molecules to treat bacterial infections has been recently raised (Ecevit et al. ref. 2022; Sun and Shahrajabian ref. 2023). In this context, this comprehensive and scholarly evidence-based review aims to cover, organize, and correlate the data accumulated from 1945 to 2023 regarding the antibacterial phenolic compounds identified from flowering plants from Asia and the Pacific. This review covers the distribution, strength, influence of molecular mass and solubility, structure-activity, mechanisms of action, synergistic activity with antibiotics, toxicity, and clinical potential. This review provides a taxonomical, phytochemical, biomolecular, and physicochemical rationale to facilitate the discovery of leads for treating bacterial infections. All data in this review was compiled from Google Scholar, PubMed, Science Direct, Web of Science, and library search, other sources were excluded. We used the following combination of keywords: ‘Phenolic compound’, ‘Plants’, and ‘Antibacterial’. Each result was examined and articles that did not contain information relevant to the topic or coming from non-peer-reviewed journals were excluded. The remaining selected articles were read critically for the information that they contained.

Non-flavonoids

Hydroxycinnamic acid derivatives

They are derived from l-phenyl alanine and are found primarily in the monocots and upper Angiosperms (Figure 1). They have weak but broad-spectrum antibacterial activity. Examples are cinnamic acid (1) from Cinnamomum zeylanicum Bl. (Lauraceae, magnoliids) and p-coumaric acid (2) (Guzman ref. 2014). Caffeic acid (3) from Plantago major L. (Plantaginaceae, lamiids) was active against Pseudomonas aeruginosa (MIC: 31.3 μg/mL) (Perumal et al. ref. 2015; Kępa et al. ref. 2018).

In upper Angiosperms, caffeic acid forms esters with quinic acid, such as chlorogenic acid (4) (Klebsiella pneumoniae) (Cai et al. ref. 2019), 3,5-di-O-caffeoylquinic acid (5), and 4,5-di-O-caffeoylquinic (6) from Lonicera japonica Thunb. (Caprifoliaceae, campanulids) which is a plant used in traditional Chinese medicine (Xiong et al. ref. 2013). Forsythiaside (7) from Forsythia suspensa (Thunb.) Vahl (Oleaceae, lamiids) inhibited the growth of E. coli, P. aeruginosa, and S. aureus with MIC values of 38.3, 38.3, and 76.6 µg/mL, respectively (Qu et al. ref. 2008). From this plant, lianqiaoxinoside B (8) was active against Bacillus dysenteriae (MIC: 36.7 µg/mL) (Kuang et al. ref. 2011). Other examples include calceolarioside B (9) from Sargentodoxa cuneata (Oliv.) Rehder and E.H. Wilson (Lardizabalaceae, eudicots) with S. aureus (MIC: 64 µg/mL), methyl 3-O-caffeoylquinate (10) with of S. aureus (MIC: 32 µg/mL) (Zeng et al. ref. 2015), and verbascoside (11) from Stachytarpheta indica (L.) Vahl (Verbenaceae, lamiids) with Enterococcus faecalis, Shigella sonnei (MIC: 31.2 µg/mL) (Nguyen et al. ref. 2018), and Staphylococcus sp. (MIC: 9.7 µg/mL) (Agampodi et al. ref. 2022).

The coupling of two caffeic acid units forms rosmarinic acid (12) in Rosmarinus officinalis L. (Lamiaceae, lamiids). Rosmarinic acid (12) has weak but broad-spectrum bactericidal activity (Abedini et al. ref. 2013). The esterification of caffeic acid forms methyl caffeate (13) in Solanum torvum Sw. (Solanaceae, lamiids) active against rifampicin-resistant M. tuberculosis (MIC: 8 μg/mL) (Balachandran et al. ref. 2012). Methoxylation of caffeic acid in position 3 gives ferulic acid (14) (Guzman ref. 2014) weakly bactericidal for S. aureus and E. coli (Cai et al. ref. 2019).

Other examples are 2-methoxy-2-butenolide-3-cinnamate (15) from Polygonum glabrum Willd. (Polygonaceae, malvids) (M. tuberculosis, MIC: 1.4 µg/mL) (Said et al. ref. 2015), coniferylaldehyde (16) from Ficus benghalensis L. (Moraceae, fabids) bactericidal for Streptococcus mutans (MIC/MBC: 62.5/62.5 µg/mL) (Meerungrueang and Panichayupakaranant ref. 2014), and nelumol A (17) from Toddalia asiatica (L.) Lam. (Rutaceae, malvids) (M. tuberculosis, MIC: 50 µg/mL) (Phatchana and Yenjai ref. 2014).

Phenylpropanoids

p-Coumaric acid (2) is the precursor of antibacterial phenylpropanoids (Yu and Jez ref. 2008) such as chavicol (18), anethole (19), and estragole (methyl chavicol) (20) (Atkinson ref. 2016) (Figure 2). Anethole (19) was weakly bactericidal against A. baumannii (Newberne et al. ref. 1999) and Bacillus cereus (MIC/MBC: 50/100 µg/mL) (Phanthong et al. ref. 2013). 1′-Acetoxychavicol acetate (21) from Alpinia galanga (L.) Willd. (Zingiberaceae, monocots) inhibited the growth of M. tuberculosis with a MIC value as low as 0.7 µg/mL (Warit et al. ref. 2017). Ferulic acid (14) is the precursor of eugenol (22) in Eugenia aromatica (L.) Baill. (Myrtaceae, malvids) active against B. cereus (MIC: 15.6 µg/mL), E. coli (MIC: 31.2 µg/mL) (Mohammed and Al-Bayati ref. 2009), and Vibrio parahaemolyticus (Ashrafudoulla et al. ref. 2020). Methylisoeugenol (23) from Daucus carota L (Apiaceae, campanulids) was effective against Campylobacter jejuni (Rossi et al. ref. 2007).

Coumarins

These chromene-2-ones originate from the ortho-hydroxylation and cyclization of cinnamic acid (1) (Shimizu ref. 2014) (Figure 3).

Simple coumarins

One of the simplest coumarins with one hydroxyl group at carbon 7 is umbelliferone (24) in Acacia nilotica (L.) Willd. ex Delile (Fabaceae, fabids) (Singh et al. ref. 2010) bactericidal for S. mutans (MIC/MBC: 15.6/15.6 µg/mL) (Meerungrueang and Panichayupakaranant ref. 2014). Addition of a hydroxyl group at carbon 8 of umbelliferone (24) forms esculetin (25) in Viola prionantha Bunge (Violaceae, fabids) active against B. cereus (MIC: 50 µg/mL) (Xie et al. ref. 2004). Methoxylation of umbelliferone (24) in position 8 produces scopoletin (26) in Pelargonium sidoides (Geraniaceae, malvids) effective against Mycobacterium smegmatis (MIC: 7.8 µg/mL) (Mativandlela et al. ref. 2007) as well as S. aureus, Enterococcus faecium, and S. maltophilia (Buathong et al. ref. 2019). Scopoletin (26) and scoparone (27) from Canarium pentatinervium Miq. (Burseraceae, malvids) were bactericidal for S. aureus with MIC/MBC values of 25/50 and 50/100 µg/mL, respectively (Mogana et al. ref. 2020; Mfonku et al. ref. 2021). Other instances are fraxetin (28) from Fraxinus rhynchophylla Hance (Oleaceae, lamiids) (S. aureus) (Wang et al. ref. 2014), 7,8-dimethoxy-6-hydroxy-coumarin (29) from Haloxylon salicornicum (Moq.) Bunge ex Boiss. (Amaranthaceae, malvids) (M. tuberculosis, MIC: 100 µg/mL) (Bibi et al. ref. 2010), and euryacoumarin A (30) from Eurya chinensis R. Br. (Pentaphylacaceae, asterids) (Song et al. ref. 2017).

Furanocoumarins

Examples are bakuchicin (31) from Psoralea corylifolia L. (Fabaceae) (Khatune et al. ref. 2004) and isoimperatorin (32) from Prangos hulusii Şenol, Yıldırım & Seçmen (Apiaceae) (MRSA, MIC: 16 µg/mL) (Tan et al. ref. 2017). Isoimperatorin (32) is antimycobacterial (Guo et al. ref. 2014).

C-Prenylated coumarins

Antibacterial coumarins with an isoprene group at carbon 6 are found in the Rutaceae family. This is the case of desmethylsuberosine (33) in Feronia lucida Teijsm. & Binn. ex Scheff. (Rahman and Gray ref. 2002). Another example is ulopterol (34) from T. asiatica with Staphylococcus epidermidis (MIC: 15.6 µg/mL) and E. coli (MIC: 62.5 µg/mL) (Raj et al. ref. 2012). The ayurvedic medicinal plant Aegle marmelos (L.) Corrêa produces xanthoarnol (35) active against E. faecalis (MIC: 18.7 µg/mL) (Chakthong et al. ref. 2012). Examples of antimycobacterial coumarins with two isoprene groups are dentatin (36), nor-dentatin (37), and clausenidine (38) in Clausena excavata Burm.f. (Sunthitikawinsakul et al. ref. 2003).

O-Prenylated coumarins

They are common in the Rutaceae and Apiaceae families. Imperatonin (39) and marmin (40) from A. marmelos inhibited the growth of M. tuberculosis with IC₅₀ values of 12.4 and 4.3 µg/mL, respectively (Chinchansure et al. ref. 2015). Similarly, 8-geranyloxy-5,7-dimethyloxycoumarin (41) from T. asiatica was antimycobacterial (Phatchana and Yenjai ref. 2014). In the Apiaceae family, Ferula pseudalliacea Rech.f. produces sanandajin (42) (S. aureus) (Dastan et al. ref. 2016).

3-Phenyl coumarins

These coumarins are found in the Fabaceae family. We can cite glycycoumarin (43) from Glycyrrhiza glabra L. with S. mutans (MIC: 12.5 µg/mL) (Demizu et al. ref. 1988) and Haemophilus influenzae (MIC: 25 µg/mL), as well as glycyrin (44) against H. influenzae and Moraxella catarrhalis (MIC: 25 µg/mL) (Tanaka et al. ref. 2001). Other examples are psoralidine (45) from P. corylifolia (Khatune et al. ref. 2004) and indicanin B (46) from Erythrina indica Lam. the latter active against S. aureus (MIC: 9.7 µg/mL) and M. smegmatis (MIC: 18.5 µg/mL) (Waffo et al. ref. 2000). Wedelolactone (47) from Eclipta alba (L.) Hassk. (Asteraceae, campanulids) inhibited the growth of S. aureus, Salmonella typhimurium, and S. epidermidis with MIC values of 20, 25, and 15 µg/mL, respectively (Dalal et al. ref. 2010).

4-Phenyl prenylated coumarins

These coumarins are prevalent in the fabids. Examples are calophyllolide (48), inophyllum C (49), and inophyllum E (50) from Calophyllum inophyllum L. (Calophyllaceae) (Yimdjo et al. ref. 2004) as well as mesuol (51) (MDR-S. aureus, MIC: 2 µg/mL) from Mesua ferrea L. (Calophyllaceae) (Verotta et al. ref. 2004). Cajanuslactone (52) from Cajanus cajan (L.) Huth (Fabaceae) was bactericidal for S. aureus (MIC/MBC: 31/125 µg/mL) (Kong et al. ref. 2010).

Benzocoumarins

Dendrobium nobile Lindl. (Orchidaceae, monocots), is an orchid used in traditional Chinese medicine that produces dendrocoumarin (53) which inhibited S. aureus, E. coli, Micrococcus tetragenus, Kocuria rhizophila, and B. cereus with MIC values of 2.5, 0.6, 5, 5 and 2.5 µg/mL, respectively (Zhou et al. ref. 2018). From this orchid, itolide A (54) was active against S. aureus, E. coli, M. tetragenus, K. rhizophila, and B. cereus with MIC values of 2.5, 1.2, 5, 10, and 1.2 µg/mL, respectively (Zhou et al. ref. 2018).

Isocoumarins

8-Hydroxy-6-methoxy-3-pentylisocoumarin (55) from Xylosma longifolia Clos (Salicaceae, fabids) (M. tuberculosis: 40.5 µg/mL) (Truong et al. ref. 2011).

Stilbenes

The condensation of one hydroxycinnamic acid unit with three malonyl-CoA units and decarboxylation gives rise to stilbenes (Abe ref. 2020; Valletta et al. ref. 2021). These are generally weakly antibacterial, but their spectrum of activity is broad (Mattio et al. ref. 2020) (Figure 4). Resveratrol (56) from Cassia grandis L.f. (Fabaceae) was bactericidal against S. aureus (MIC: 125/125 µg/mL), E. coli (MIC: 50/125 µg/mL) (Kusumaningtyas et al. ref. 2020), S. mutans (50/50 µg/mL), and S. sanguis (50/100 µg/mL) (Yim et al. ref. 2010). Resveratrol (56) was bacteriostatic for a panel of Gram-positive bacteria (Paulo et al. ref. 2010). Hydroxylation of resveratrol (56) at carbon 3′ forms piceatannol (57), which was bactericidal for S. aureus (MIC/MBC: 125/125 µg/mL) and E. coli (MIC/MBC: 100/125 µg/mL) (Kusumaningtyas et al. ref. 2020). Methoxylation of resveratrol (56) at positions 3 and 5 gives rise to pterostilbene (58), which was bactericidal for B. cereus (MIC: 25 µg/mL) (Shih et al. ref. 2021). Smiglastilbene (59) from Smilax glabra Roxb. (Smilacaceae, monocots) was weakly active against Gram-positive bacteria (Xu et al. ref. 2013). Rhaponticin (60) from Rheum rhaponticum L. (Polygonaceae, malvids) was weakly bactericidal against M. tuberculosis (MIC/MBC: 128/256 µg/mL) (Smolarz et al. ref. 2013). The methoxylation of stilbenes increases their antibacterial strength. This is observable with 3-hydroxy-5-methoxystilbene (61) from P. glabrum (M. tuberculosis, MIC: 3.3 µg/mL) (Said et al. ref. 2015). An increase in activity is also observed when stilbenes are prenylated as in the case of cajanin stilbene acid (62) from C. cajan with S. epidermidis (MIC/MBC: 13/100 µg/mL), S. aureus (MIC/MBC: 25/105 µg/mL), and Bacillus subtilis (MIC/MBC: 25/250 µg/mL) (Kong et al. ref. 2010). Cajanin stilbene acid (62) was active against VRE with a MIC as low as 1 µg/mL. Interestingly, intravenous administration of cajanin stilbene at a dose of 5 mg/kg per day for 7 days resulted in a 90% survival rate in rodents infected with VRE (Tan, Hua, et al. ref. 2020).

Dihydrostilbenes

Reduction of the Δ^7,7′ double bond of stilbenes forms antibacterial dihydrostilbenes in monocots. We can cite for instance dihydropinosylvine (63) from Dioscorea batatas Decne. (Dioscoreaceae, Monocots) (Takasugi et al. ref. 1987) and the phytoalexin desmethylbatatasin IV (64) (P. aeruginosa, MIC: 10 µg/mL) (Fagboun et al. ref. 1987; Adesanya et al. ref. 1989). Bletilla striata (Thunb.) Rchb. F. (Orchidaceae) which is used in traditional Chinese medicine, produces batatasin III (65) as well as an unusual type of dihydrostilbenes with ethylbenzene groups, namely bulbocol (66), shanciguol (67), and shancigusine B (68) active against S. aureus with MIC values of 9, 7, and 3 µg/mL, respectively (Jiang et al. ref. 2019).

Oligostilbenes

Plants of the family Vitaceae (Rosids) and Dipterocarpaceae (Malvids) use resveratrol (56) to construct oligostilbenes active against Gram-positive bacteria. ɛ-Viniferin (69) from Vitis amurensis Rup. (Vitaceae) was bacteriostatic for MRSA (MIC: 50 µg/mL) (Basri et al. ref. 2014) and bactericidal for S. mutans and S. sanguis with MIC/MBC values of 25/50 and 50/50 µg/mL, respectively (Yim et al. ref. 2010). Other examples include balanocarpol (70), vaticanol B (71) (Sahidin et al. ref. 2017), and flexuosol A (72) from Dryobalanops lanceolata Burck (Dipterocarpaceae) (Wibowo et al. ref. 2011). We can also cite dehydro-δ-viniferine (73) from Dryobalanops rappa Becc (Wibowo et al. ref. 2022) bacteriostatic for S. aureus (MIC/MBC: 2/16 µg/mL) (Mattio et al. ref. 2019).

Miscellaneous

The prenylated stilbene derivative lakoochin A (74) from Artocarpus lakoocha Wall. ex Roxb. (Moraceae) inhibited the growth of M. tuberculosis (MIC: 12.5 µg/mL) (Puntumchai et al. ref. 2004).

Diarylheptanoids

The addition of two units of p-coumaric acid (2) or ferulic acid (14) with one malonyl-CoA unit forms antibacterial diarylheptanoids (Abe ref. 2020) such as curcumin (75) in Curcuma longa L. (Zingiberaceae) (Gunes et al. ref. 2016). The cyclic diaryheptanoid engelhardione (76) from Engelhardia roxburghiana Wall. (Juglandaceae, fabids) inhibited the growth of M. tuberculosis with the MIC value of 2 µg/mL (Lin et al. ref. 2005) (Figure 5).

Lignans

These phenolic compounds come from the coupling of two phenylpropanoid units between carbons 8 and 8′ (Lewis and Davin ref. 1999; Satake et al. ref. 2015) (Figure 6).

Tetrahydrofurans

Ammaniol (77) from Ammannia multiflora Roxb. (Lythraceae, malvid) inhibited the growth of M. tuberculosis (MIC: 25 µg/mL) (Upadhyay et al. ref. 2012). Nectandrine B (78) from Myristica fragrans Houtt. (Myristicaceae, magnoliids) was active against Pseudomonas syringae (IC₅₀: 63 µg/mL) (Cho et al. ref. 2007).

Furanofurans

In upper Angiosperms, examples are syringaresinol (79) from Canthium horridum Bl. (Rubiaceae, lamiids) (Yang et al. ref. 2010) and ecbolin A (80) in Ecbolium viride (Forssk.) Alston (Acanthaceae, lamiids) (S. aureus, MIC: 7.8 µg/mL) (Cecilia et al. ref. 2012).

Dibenzylbutanes

Macelignan (81) from M. fragrans was bactericidal against S. mutans (MIC/MBC: 3.9/7.8 µg/mL) (Chung et al. ref. 2006). From this plant, erythro-austrobailignan-6 (82) and meso-dihydroguaiaretic acid (83) inhibited the growth of Agrobacterium tumefaciens with IC₅₀ values of 17 and 23 µg/mL, respectively (Cho et al. ref. 2007). erythro-Austrobailignan-6 (82) was active against MRSA and MDR-M. tuberculosis with the MIC values of 50 µg/mL, respectively (Reyes-Melo et al. ref. 2017).

Dibenzylbutyrolactones

Examples are meridinol (84) in Lasia spinosa (L.) Thwaites (Araceae, monocots) (Hasan et al. ref. 2011) as well as (−)-nortrachelogenin (85) from Patrinia scabisifolia Link (Caprifoliaceae, campanulids), the latter being active against E. coli O157:H7 (Lee, Ji, et al. ref. 2016).

Dibenzocyclooctadienes

Manglisin B (86) from Manglietiastrum sinicum Y.W. Law (Magnoliaceae, magnoliids) (Ding et al. ref. 2014; Qiang et al. ref. 2022).

Aryltetralins

Schizandriside (87) from Acer truncatum Bunge (Sapindaceae, malvids) developed an inhibition zone against S. aureus (2 µg/disc) (Dong et al. ref. 2006; Shen et al. ref. 2022).

Neolignans

These lignans come from the coupling of two phenylpropanoid units between carbons other than 8 and 8′ (Teponno et al. ref. 2016) (Figure 7).

Benzodioxanes

Melaleucin A (88) from Melaleuca bracteata F. Muell. (Myrtaceae, malvids) inhibited the growth of MRSA (MIC: 8 µg/mL) (Li et al. ref. 2017).

Dihydrobenzofuran lignans

The 8-5′ coupling of two phenylpropanoid units (Wang, Wang, et al. ref. 2022) yields dihydrobenzofuran lignans which have broad-spectrum antibacterial effects. An example is glochidioboside (89) in the genus Glochidion J.R. Forst. & G. Forst. (Phyllanthaceae, fabids) which inhibited the growth of E. coli O157:H7 (Lee, Woo, et al. 2015).

Biphenyl lignans

The coupling of two phenylpropanoid units between carbons 3 and 3′ forms biphenyl lignans mostly found in the Magnoliaceae family. Examples are magnolol (90) and honokiol (91) in Magnolia officinalis Rehder & E.H. Wilson active against Gram-positive bacteria (Ho et al. ref. 2001). Honokiol (91) was bactericidal against S. aureus, B. subtilis, Propionibacterium acnes, and Propionibacterium granulosum with MIC/MBC values of 13.1/26.6, 8.2/16.7, 4.1/16.7, and 8.2/16.7 µg/mL, respectively (Kim et al. ref. 2010) as well as MRSA (MIC: 12.5 µg/mL) (Syu et al. ref. 2004). From M. officinalis, piperitylmagnolol (92) gave MIC values of 12.5, 6.2, 6.2, and 6.2 µg/mL with S. aureus, MRSA, E. faecalis, and VRE, respectively, and was bactericidal against VRE (Syu et al. ref. 2004). Other examples are 3,5′-diallyl-2′-hydroxy-4-methoxybiphenyl (93) from Magnolia grandiflora L. (Clark et al. ref. 1981). In the family Moraceae, an example is (7′R,8′S)-4,4′-dimethoxy-strebluslignanol (94) from Streblus asper Lour. (Moraceae) (Nie et al. ref. 2016).

Miscellaneous lignans

These antibacterial lignans are abundant in basal Angiosperms and include cinchonain Ib (95) from S. glabra (Xu et al. ref. 2013), manglisin A (96) from M. sinicum (Ding et al. ref. 2014), and the biphenyl ether lignan obovatol (97) from Magnolia obovata Aiton (Magnoliaceae) (Ito et al. ref. 1982).

Hydroxybenzoic acid derivatives

They derive from the shikimate pathway (Ossipov et al. ref. 2003) and have a broad spectrum of antibacterial activity (Figure 8). One of the simplest examples is 4-hydroxybenzoic acid (98) from Oryza sativa L. (Poaceae, monocots) (Cho et al. ref. 1998). Further addition of hydroxyl groups at positions 3 and 5 forms gallic acid (99) active against S. aureus, MRSA (MIC: 64 µg/mL), M. tuberculosis (MIC: 66.6 µg/mL) (Deng et al. ref. 2013), and S. epidermidis (Adesina et al. ref. 2000). Methyl gallate (100) from Rhus chinensis Mill. (Anacardiaceae, malvids) was active against P. aeruginosa and E. coli with MIC values of 12.5 and 25 µg/mL, respectively (Saxena et al. ref. 1994) as well as against S. aureus (MIC: 7.8 µg/mL) (Xu et al. ref. 2015), Vibrio cholerae (MIC: 30 µg/mL) (Sánchez et al. ref. 2013), Salmonella typhi (MIC: 3.9 µg/mL) (Choi et al. ref. 2014), and M. tuberculosis (MIC: 50 µg/mL) (Hernández-García et al. ref. 2019). Methyl gallate (100) was weakly bactericidal against Shigella dysenteriae (MIC/MBC: 128/256, µg/mL) (Acharyya et al. ref. 2015) and K. pneumoniae (MIC/MBC: 100/300 µg/mL (Li, Lin, et al. ref. 2016). From Rhus glabra L. (Anacardiaceae), 4-methoxy-3,5-dihydroxybenzoic acid (101) was broadly antibacterial (Saxena et al. ref. 1994).

In the family Saxifragaceae (core eudicots), Saxifraga melanocentra Franch. produces ethyl gallate (102) which is bactericidal against K. pneumoniae (Li, Lin, et al. ref. 2016). Methoxylation of gallic acid (99) at positions 3 and 5 forms syringic acid (103) in Ardisia elliptica Thunb. (Myrsinaceae, asterids) active against S. typhimurium (MIC: 62.5 µg/mL) (Phadungkit and Luanratana ref. 2006).

Protocatechuic acid (104) (Metsämuuronen and Sirén ref. 2019) from Arbutus unedo L. (Ericaceae, asterids) was active against A. baumannii (Liu et al. ref. 2005), while protocatechuic acid ester (105) from Arachis hypogaea L. (Fabaceae) was weakly active against S. aureus (Miklasińska et al. ref. 2015). Protocatechuic acid (104) is the precursor of vanillic acid (106) (Metsämuuronen and Sirén ref. 2019) which was active against M. tuberculosis (MIC: 83.3 µg/mL) (Deng et al. ref. 2013).

Miscellaneous simple phenolic compounds

Examples are arbutin (107) and hydroquinone (108) from A. unedo (Jurica et al. ref. 2017) (Figure 9), thymol (109) from Thymus vulgaris L. (Lamiaceae) (E. coli, MIC: 8 µg/mL) (Xu et al. ref. 2008), 4-hydroxybenzaldehyde (110) from Alpinia conchigera Griff. (Zingiberaceae) (Aziz et al. ref. 2012), syringaldehyde (111) from Juglans regia L. (Juglandaceae) (Colaric et al. ref. 2005) (S. mutans, MIC/MBC: 62.5/62.5 µg/mL) (Meerungrueang and Panichayupakaranant ref. 2014), 3,3′-methylene-bis(4-hydroxybenzaldehyde) (112) from S. asper (B. subtilis, MIC: 27 µg/mL) (Nie et al. ref. 2016), ellagic acid (113) (Ghudhaib et al. ref. 2010), 3,3′,4,4′,5′-pentamethylcoruleoellagic acid (114) from Rhodamnia dumetorum (DC.) Merr. and L.M Perry (Haemophilus influenza, MIC: 9.3 µg/mL) (Lakornwong et al. ref. 2018; Munvera et al. ref. 2020), hydroxytyrosol (115) from S. cuneata (S. aureus, MIC: 2 µg/mL) (Zeng et al. ref. 2015), and cinnamaldehyde (116) in Cinnamomum cassia (L.) J. Presl (Lauraceae) (Firmino et al. ref. 2018).

Benzoquinones

Phenolic compounds in this group are generally strongly antibacterial (Figure 10). Examples are 2,6-dimethoxy-1,4-benzoquinone (117) from Ficus foveolata Pittier (Moraceae) bactericidal for S. mutans (MIC/MBC: 7.8/7.8 µg/mL) (Nishina et al. ref. 1991; Meerungrueang and Panichayupakaranant ref. 2014) and thymoquinone (118) from Nigella sativa L. (Ranunculaceae, eudicots) (Dey et al. ref. 2014) bactericidal for Listeria monocytogenes (MIC: 8/8 µg/mL) and S. aureus (MIC/MBC 8/16 µg/mL) (Chaieb et al. ref. 2011) and active against E. coli (Cetin-Karaca and Newman ref. 2015). Another example is abruquinone B (119) from Abrus precatorius L. (Fabaceae) (M. tuberculosis, MIC: 12.5 µg/mL) (Limmatvapirat et al. ref. 2004). Pulsaquinone (120) from Pulsatilla koreana (Yabe ex Nakai) Nakai ex T. Mori (Ranunculaceae) was active against P. acnes, B. subtilis, S. aureus, S. mutans, P. aeruginosa, and S. sonnei with the MIC values of 2, 2.7, 2, 2, 3.3, and 2 µg/mL, respectively (Cho et al. ref. 2009).

Plants of the Myrsinaceae family produce antibacterial benzoquinones substituted with long-chain alkyl groups, such as embelin (121) from Embelia ribes Burm.f. bactericidal for S. aureus (MIC/MBC: 20/75 µg/mL) (Chitra et al. ref. 2003; Radhakrishnan et al. ref. 2011), rapanone (122) in Ardisia crenata Sims (Podolak et al. ref. 2021), and ardisiaquinone B (123) from Ardisia sieboldii Miq. (Enterobacter aerogenes, MIC: 16 µg/mL) (Ogawa and Shinsaku ref. 1968; Omosa et al. ref. 2016).

1,4-Naphthoquinones

Simple 1,4-naphthoquinones

Simple 1,4-naphthoquinones originate from the polyketide or shikimate pathways (Widhalm and Rhodes ref. 2016). These are among the most potent known antibacterial compounds found in Angiosperms (Figure 11). An example is juglone (124) (Zmantar et al. ref. 2016), bacteriostatic against Streptococcus pyogenes (MIC/MBC: 1.5/100 µg/mL) (Macé et al. ref. 2017) and active against M. smegmatis (MIC: 0.7 µg/mL) (Clark et al. ref. 1990). 3-Methoxyjuglone (125) from E. roxburghiana was active against M. tuberculosis with a MIC as low as 0.2 µg/mL (Lin et al. ref. 2005). 2-Methoxy-1,4-naphthoquinone (126) (lawsone methyl ether) from Impatiens balsamina L. (Balsaminaceae, asterids) inhibited the growth of Aeromonas salmonicida and MRSA with MIC values of 2 and 15.6 μg/mL, respectively (Yang et al. ref. 2001).

The condensation of one acetyl-CoA unit with five malonyl-CoA units forms naphthoquinones with strong antibacterial effects in the order Ericales (asterids). An example is plumbagin (127) from Diospyros kaki Thunb. (Ebenaceae) (Lee and Lee ref. 2008) active against S. epidermidis (MIC: 0.7 µg/mL) (Jeyachandran et al. ref. 2009), Neisseria gonorrhoae (MIC: 19.5 µg/mL) (Kuete et al. ref. 2009), Gardnerella vaginalis (Sobhani et al. ref. 2018), MDR-M. tuberculosis (MIC/MBC: 0.2/1.5 µg/mL), and bactericidal for Proteus vulgaris (MIC/MBC: 16/16 µg/mL) (Dey et al. ref. 2014). Plumbagin (127) was bactericidal for M. smegmatis and M. tuberculosis (MIC/MBC: 4.8/9.7 µg/mL) (Kuete et al. ref. 2009). From D. kaki, 2-methoxy-7-methyl juglone (128) (Gu et al. ref. 2004) inhibited the growth of M. tuberculosis with a MIC as low as 0.5 µg/mL (selectivity index: 30.2) (Mahapatra et al. ref. 2007). Diospyros maritima Bl. (Ebenaceae) yields 7-methyljuglone (129) active against M. tuberculosis (MIC: 0.5 µg/mL) (Bapela et al. ref. 2006) and bacteriostatic for M. smegmatis (MIC/MBC: 1.5/15.6 µg/mL) (McGaw et al. ref. 2008). D. maritima produces droserone (130) which inhibited the growth of pan-resistant Mycobacterium tuberculosis (clinical isolate CIBIN 99) with the MIC value of 25 µg/mL) (Uc-Cachón et al. ref. 2014). Chimaphilin (131) from Monenes uniflora L. (Ericaceae) was active against S. aureus (MIC: 25 µg/mL) (Saxena et al. ref. 1996) and M. tuberculosis (IC₅₀: 5.4 µg/mL) (Li et al. ref. 2018).

1,4-Naphthoquinones oligomers

These phenolic compounds are produced from the oxydative coupling of naphthoquinones in the Ebenaceae (Figure 11). Examples of dimers of plumbagin (127) are maritinone (132), chitranone (133), zeylanone (134), and 3,3′-biplumbagin (135) in D. maritima (Gu et al. ref. 2004) which inhibited pan-resistant M. tuberculosis (clinical isolate CIBIN 99) with the MIC values of 3.1, 3.1, 12.5, and 3.1 µg/mL, respectively (Uc-Cachón et al. ref. 2014). Of note, the selectivity indexes of maritinone (132) and 3,3′-biplumbagin (135) were 74.3 and 194.1, respectively (Uc-Cachón et al. ref. 2014).

Diospyrin (136) formed from the coupling between a pair of 7-methyljuglone (129) is active against Corynebacterium dyphtheriae (MIC: 3.1 µg/mL) (Adeniyi et al. ref. 2000) and bacteriostatic for Mycobacterium bovis (MIC/MBC: 1.7/39 µg/mL) (McGaw et al. ref. 2008). Likewise, isodiospyrin (137) inhibited Streptococcus pneumoniae with a MIC value as low as 0.7 µg/mL (McGaw et al. ref. 2008). An example of 1,4-naphthoquinone dimer coupled with coumarins is diospyrone (138) active against MDR-K. pneumoniae and MDR-P. aeruginosa (Kuete et al. ref. 2009).

Prenylated 1,4-naphthoquinones

Lamiids and plants of the Boraginaceae family combine a 4-hydroxybenzoic acid unit with a geranyl group to form antibacterial prenylated 1,4-naphthoquinones with naphthazarin scaffolds (Rajbhandari et al. ref. 2007). This is the case of shikonin (139) and deoxyshikonin (140) from Lithospermum erythrorhizon Siebold & Zucc. used in traditional Chinese medicine (Brigham et al. ref. 1999). Shikonin (139) from Arnebia euchroma (Royle ex Benth.) I.M. Johnst. was bactericidal against MRSA (MIC/MBC: 6.2/12.5 µg/mL) (Shen et al. ref. 2002). In the Bignoniaceae family, an example is lapachol (141) from Oroxylum indicum (L.) Kurz (Bignoniaceae) (Ali et al. ref. 1998).

Anthraquinones

Simple anthraquinones

Angiosperms produce antibacterial anthraquinones from the polyketide or shikimate pathways (Figure 12). For example, chrysophanol (142) from R. rhaponticum, formed by the addition of one acetyl-CoA unit to seven malonyl-CoA units, was bactericidal against M. tuberculosis (64/128 µg/mL) (Smolarz et al. ref. 2013) and active against S. epidermidis (MIC: 31.2 µg/mL) (Coopoosamy and Magwa ref. 2006a). The oxidation of chrysophanol (142) at carbon 3 forms aloe-emodin (143) in R. rhaponticum (Coopoosamy and Magwa ref. 2006b; Alaadin et al. ref. 2007; Lee, Kang, et al. ref. 2010). Aloe-emodin (143) was active against MRSA (MIC: 2 µg/mL) (Hatano et al. ref. 1999; Alaadin et al. ref. 2007), S. mutans (MIC: 1.2 µg/mL) (Zheng et al. ref. 2011), and bactericidal for M. tuberculosis (MIC/MBC: 64/128 µg/mL) (Smolarz et al. ref. 2013). The oxidation of aloe-emodin (143) at carbon 3 forms rhein (144) in Rheum officinale Baill. (Polygonaceae) effective against MRSA (MIC: 15.6 µg/mL) (Joung et al. ref. 2012), Bacteroides fragilis (MIC: 1.5 µg/mL) (Cyong et al. ref. 1987), and Porphyromonas gingivalis (MIC: 2.5 µg/mL) (Azelmat et al. ref. 2015).

Another example is emodin (145) from Cassia alata L. (Fabaceae) with methicillin-sensitive S. aureus (MIC: 25 µg/mL) (Joung et al. ref. 2012), S. aureus (MIC: 8 µg/mL) (Yan et al. ref. 2017), MRSA (MIC: 1.5 µg/mL) (Promgool et al. ref. 2014), M. tuberculosis (MIC/MBC: 4/8 µg/mL) (Dey et al. ref. 2014), B. cereus (MIC/MBC: 8/8 µg/mL) (Dey et al. ref. 2014), and Haemophilus parasuis (MIC/MBC: 32/64 µg/mL) (Li, Song, et al. ref. 2016).

In the family Rubiaceae, examples are damnacanthal (146) from Morinda elliptica (Hook.f.) Ridl. (M. tuberculosis, MIC: 13 μg/mL) (Pollo et al. ref. 2020), 1,8-dihydroxy-2-methyl-3,7-dimethoxyanthraquinone (147) from Morinda angustifolia Roxb. (Xiang et al. ref. 2008), 1-hydroxy-2-methoxycarbonyl-anthraquinone (148) from Coptosapelta flavescens Korth. (MRSA, MIC: 16 µg/mL) (Kongyen et al. ref. 2014), and rubiadin (149) from Rubia tinctoria L. (S. aureus, MIC: 32 µg/mL) (Comini et al. ref. 2011).

6-Methyl-1,4-dihydroxyanthraquinone (150) from Tectona grandis L.f. (Verbenaceae) was bacteriostatic for Klebsiella aerogenes (16/128 µg/mL) (Bitchagno et al. ref. 2015).

Miscellaneous anthraquinones

T. grandis produces an unusual dimer of anthraquinone and naphthoquinone: tectograndone (151), bactericidal for E. coli (MIC/MBC: 32/128 µg/mL) (Bitchagno et al. ref. 2015). Revandchinone-3 (152) from Rheum emodi Wall. (Polygonaceae) inhibited the growth of a broad spectrum of bacteria (Babu et al. ref. 2003).

Tannins

Proanthocyanidins

The coupling of two catechin and or epigallocatechin units forms proanthocyanidins (Figure 13). These phytoanticipins are weakly antibacterial but their spectrum of activity is broad. An example is cinnamtanin B1 (153) from Vaccinium vitis-idaea L. (Ericaceae) against P. gingivalis and Prevotella intermedia (MIC: 100 µg/mL) (Ho et al. ref. 2001). Another illustration is (+)-epigallocatechin-(2β→O→7, 4β→8)-(+)-catechin (154) from Quercus ilex L (Fagaceae, fabids) (Karioti et al. ref. 2011). The antibacterial spectrum of proanthocyanidin oligomers and polymers is limited to Gram-positive bacteria as in ZP-CT-A from Zanthoxylum piperitum DC (Rutaceae) (MRSA, MIC: 128 µg/mL) (Kusuda et al. ref. 2006), theasinensin A. (155) and B (156) (MRSA, MIC: 64 µg/mL) (Hatano et al. ref. 2003), and proanthocyanidins from Diospyros kaki L. (Ebenaceae) (Wang et al. ref. 2020).

Gallotannins

The esterification of a glucose unit by several units of gallic acid (99) forms gallotannins (Ossipov et al. ref. 2003). These phytoanticipins are weakly antibacterial and include 1,2,3,4,6-penta-O-galloyl-β-d-glucose (157) from A. truncatum (S. aureus, MIC: 60 µg/mL) (Zhang et al. ref. 2008; Lin et al. ref. 2011) and tannic acid (158) from Alnus japonica (Thunb.) Steud. (Betulaceae, fabids) (Wu et al. ref. 2010).

Ellagitannins

Ellagitannins result from the coupling of two adjacent units of gallic acid (99) within gallotannins and generally have weak but broad-spectrum antibacterial activities (Figure 13) (Al-Harbi et al. ref. 2017). These tannins are found in fabids and include, for example, corilagin (159) and geraniin (160) from Acalypha wilkesiana Müll. Arg. (Euphorbiaceae) active against S. aureus with MIC values of 50 and 25 µg/mL, respectively (Adesina et al. ref. 2000). Corilagin (159) was active against E. coli (MIC: 62.5 µg/mL) (Li et al. ref. 2013) and geraniin (159) with Vibrio vulficus (MIC: 25 µg/mL) (Taguri et al. ref. 2006). In the malvids, examples are castalagin (161) from Terminalia catappa L. (Combretaceae) (Clostridium perfringens, MIC: 67 µg/mL) (Taguri et al. ref. 2006) and punicalagin (162) (S. aureus, MIC: 250 µg/mL) from Punica granatum L. (Lythraceae) (Xu et al. ref. 2017; Li et al. ref. 2020). The oligomeric ellagitannin isorugosin A from Liquidambar formosana Hance (Altingiaceae, core eudicots) was active against MRSA (Shimozu et al. ref. 2017).

Miscellaneous phenolic compounds

Long-chain alkyl phenols

These phenolic compounds originate from the polyketide pathway and are strongly active against Gram-positive bacteria (Sampietro et al. ref. 2013) (Figure 14). In the basal Angiosperms, magnoliids produce antibacterial alkylresorcinols, such as knerachelin B (163) from Knema furfuracea (Hook.f. and Thomson) Warb. (Myristicaceae) (S. aureus, MIC: 4 µg/mL) (Zahir et al. ref. 1993), malabaricone A (164) (S. aureus, MIC: 0.5 µg/mL, bactericidal, selectivity index ≥ 80), and malabaricone B (165) (MRSA, MIC: 0.5 µg/mL, selectivity index ≥ 80) (Sivadas et al. ref. 2023). Malabaricone B (165) inhibited the growth of VRE and MRSA with MIC values as low as 1 µg/mL and was bactericidal against MRSA (Sivadas et al. ref. 2023). Myristica fragrans produces malabaricone C (166) active against S. aureus (MIC: 4 µg/mL) (Orabi et al. ref. 1991). In monocots, Zingiber officinale Roscoe (Zingiberaceae) produces antibacterial alkyl catechols, such as [6]-gingerol (167), [10]-gingerol (168), and [12]-gingerol (169) (Hiserodt et al. ref. 1998; Park et al. ref. 2008).

Anacardic acid (170) from Anacardium occidentale L. (Anacardiaceae) inhibited the growth of S. mutans and P. acnes with MIC values as low as 1.5 and 0.7 µg/mL, respectively (Kubo et al. ref. 1993). Other long-chain alkyl phenols of this kind have been identified in Semecarpus anacardium L.f. (Anacardiaceae) (Sundaram et al. ref. 2014).

In upper Angiosperms, Ardisia cornudentata Mez (Myrsinaceae) produces 1-(3,5-dihydroxyphenyl)nonan-1′-one (171), belamcandol (172), and 3-methoxy-2-methyl-5-pentylphenol (173) which inhibited the growth of M. tuberculosis with MIC values of 6, 33.8, and 2.5 µg/mL, respectively (Chang et al. ref. 2011). Cannabis sativa L (Cannabaceae, fabids) produce cannabidiol (174) and cannabigerol (175) active against S. aureus with MIC values as low as 0.5 and 1 µg/mL, respectively (Appendino et al. ref. 2008; Radwan et al. ref. 2009). Cannabidiol (174) inhibited the growth of E. faecium, M. catarrhalis, N. gonorrhoeae, Neisseria meningitidis, Legionella pneumophila, and A. baumannii with MIC values of 0.5, 1, 1, 0.2, 1, and 64 µg/mL, respectively (Blaskovich et al. ref. 2021). Cannabidiol (174) applied topically could treat MRSA-infected mice but was inactive when given orally (Blaskovich et al. ref. 2021). Aerva sanguinolenta (L.) Bl. (Amaranthaceae) produces bakuchiol (176) active against S. mutans with a MIC as low as 0.9 µg/mL (Rao et al. ref. 2012) as well as Mycobacterium aurum (MIC: 15. 9 µg/mL) (Newton et al. ref. 2002).

Prenylated phloroglucinols

Fabids, and to a lesser extent malvids, produce prenylated phloroglucinols active against Gram-positive bacteria (Figure 15). In the family Hypericaceae, examples are chinesin I (177) from Hypericum japonicum Thunb. (S. aureus, MIC: 3.1 µg/mL) (Nagai and Tada ref. 1987) as well as hyperjaponicol C (178) (Li et al. ref. 2018), and olympicin A (179) from Hypericum olympicum L. (Shiu et al. ref. 2012). Hypercalin A (180) and hypercalin B (181) from Hypericum acmosepalum N. Robson inhibited S. aureus (expressing NorA) with MIC values as low as 2 and 0.5 µg/mL, respectively (Osman et al. ref. 2012).

Other examples are, in the fabids, rottlerin (182) from Mallotus philippensis (Lam.) Müll. Arg. (Euphorbiaceae) (Pandey et al. ref. 2016), lupulone (183) from Humulus lupulus L. (Cannabaceae) (MRSA, MIC: 0.6 µg/mL) (Bocquet et al. ref. 2019), as well as calophynic acid (184) and brasiliensic acid (185) from C. inophyllum (Yimdjo et al. ref. 2004). In the family Myrtaceae, rhodomyrtone (186), isomyrtucommulone B (187), and myrciarone B (188) from Myrciaria dubia (Kunth) McVaugh inhibited B. subtilis with the MIC values of 0.7, 1.5, and 1.5 µg/mL, respectively (Kaneshima et al. ref. 2017). Callistemenonone A (189) from Callistemon viminalis (Sol. ex Gaertn.) G. Don was bactericidal for B. cereus (MIC/MBC: 5/20 µg/mL) (Xiang et al. ref. 2017).

Prenylated acetophenones

Meliviticine A (190) from Melicope viticina (Wall. ex Kurtz) T.G. Hartley (Rutaceae) inhibited the growth of MRSA, S. typhi, and P. aeruginosa (MIC: 50 µg/mL) (Li et al. ref. 2019) (Figure 16).

Prenylated benzophenones

The addition of one benzoyl-CoA unit with three malonyl-CoA units and substitutions with dimethylallyl groups form prenylated benzophenones (Abe ref. 2020). They are active against Gram-positive bacteria and are found in the family Clusiaceae (fabids) (Figure 17). Cowanone (191) from Garcinia cowa Roxb. inhibited the growth of MRSA with a MIC value as low as 0.5 µg/mL (Trisuwan and Ritthiwigrom ref. 2012). Garcinia multiflora Champ. ex Benth. produces chamuangone (192) bactericidal for S. pyogenes (MIC/MBC: 7.8/31.2 µg/mL) (Sakunpak and Panichayupakaranant ref. 2012) as well as garcimultiflorone A (193) (Chen et al. ref. 2008).

Prenylated xanthones

Internal coupling of benzophenones forms a wide range of antibacterial prenylated xanthones in the Hypericaceae, Calophyllaceae, and Clusiaceae families (Figure 18). In the Hypericaceae family, examples are isocudraniaxanthone B (194), isojacareubine (195) bactericidal against MRSA (SCCmec III) (MIC/MBC: 4/16 µg/mL) (Zuo et al. ref. 2012), and cochinchinone A (196) (P. aeruginosa, MIC: 4.7 µg/mL) from Cratoxylum cochinchinense (Lour.) Bl. (Boonnak et al. ref. 2009). Other examples are gerontoxanthone I (197) and 9-hydroxycalabaxanthone (198) from Cratoxylum formosum (Jack) Benth. & Hook.f. ex Dyer (S. typhi, MIC: 1.1 µg/mL) (Boonsri et al. ref. 2006). Caloxanthone A (199) from C. inophyllum was active against S. aureus (Yimdjo et al. ref. 2004).

Thai researchers have identified in plants of the Garcinia L. genus (Clusiaceae) a plethora of antibacterial xanthones that have often in common dimethylallyl groups at position 1 and or 7. This is the case for 12b-hydroxy-des-d-garcigerrin A (200) from Garcinia dulcis (Roxb.) Kurz bacteriostatic for MRSA (MIC/MBC: 4/>200 µg/mL) (Thepthong et al. ref. 2017). Garcinia mangostana L. produces α-mangostin (201) (Nguyen and Marquis ref. 2011) active against VRE (MIC: 3.1 µg/mL) (Sakagami et al. ref. 2005), B. subtilis (MIC: 0.5 µg/mL) (Auranwiwat et al. ref. 2014), S. typhimurium (Yahayu et al. ref. 2013), and P. acnes (MIC: 0.7 µg/mL) (Al-Massarani et al. ref. 2013; Ahmad et al. ref. 2019). α-Mangostin (201) and β-mangostin (202) inhibited M. tuberculosis (MIC: 6.2 µg/mL) as well as garcinone B (203) (MIC: 12.7 µg/mL) (Suksamrarn et al. ref. 2003). β-Mangostin (202) was active against B. cereus with a MIC value as low as 0.2 µg/mL (Auranwiwat et al. ref. 2014). γ-Mangostin (204) inhibited the growth of MRSA and VRE with MIC values of 3.1 and 6.2 µg/mL, respectively (Dharmaratne et al. ref. 2013). Garcinone C (205) was antileptospiral (Seesom et al. ref. 2013). We can also mention garcicowanone A (206), rubraxanthone (207), fuscaxanthone A (208), 9-hydroxycalabaxanthone (198), and garcinianone A (209) from G. cowa, active against B. subtilis with the MIC values of 0.2, 1, 8, 4, and 4 µg/mL, respectively (Trisuwan and Ritthiwigrom ref. 2012; Auranwiwat et al. ref. 2014). From this plant, cowanol (210), cowanin (211), and garciniacowone (212) inhibited S. aureus with MIC values of 2, 4, and 2 µg/mL, respectively. Cowanol (210) was effective against E. coli (MIC: 8 µg/mL) (Siridechakorn et al. ref. 2012) and yielded a MIC value of 2 µg/mL against MRSA (Siridechakorn et al. ref. 2012; Trisuwan and Ritthiwigrom ref. 2012). Other examples are nigrolineaxanthone F (213), brasilixanthone (214) (MRSA, MIC: 2 µg/mL) (Rukachaisirikul, Tadpetch, et al. ref. 2005), 3-hydroxyblancoxanthone (215) (B. cereus, MIC: 4 µg/mL), nigrolineaxanthone Q (216) (Micrococcus luteus, MIC: 8 µg/mL) (Raksat et al. ref. 2019), 8-desoxygartanin (217) (S. aureus, MIC: 16 µg/mL), ananixanthone (218) (S. aureus, MIC: 32 µg/mL), and nigrolineaxanthone N (219) (MRSA, MIC: 4 µg/mL) from Garcinia nigrolineata Planch. ex T. Anderson (Rukachaisirikul et al. ref. 2003). Garcinia scortechinii King produces nigrolineaxanthone G (220) and 6-deoxyjacareubin (221) (MRSA, MIC: 4 µg/mL) (Rukachaisirikul, Tadpetch, et al. ref. 2005).

The internal cyclization of dimethylallyl groups forms caged xanthones, such as moreollic acid (222) from Garcinia hanburyi Hook.f. (MRSA, MIC: 25 µg/mL), as well as morellic acid (223) (Sukpondma et al. ref. 2005) and gambogic acid (224) bactericidal for MRSA (USA300) with the MIC/MBC of 12.5/25 and 25/50 µg/mL, respectively (Chaiyakunvat et al. ref. 2016). From G. scortechinii, scortechinone B (225), C (226), and F (227) were active against S. aureus with the MIC of 2, 8, and 4 µg/mL, respectively (Rukachaisirikul, Phainuphong, et al. ref. 2005).

Non-prenylated and hydroxylated xanthones have milder activities as in 1,5,6-trihydroxyxanthone (228) from Garcinia succifolia Kurz (S. aureus, MIC: 64 µg/mL) (Duangsrisai et al. ref. 2014). In the family Moraceae, gerontoxanthone H (229) from Cudrania cochinchinensis (Lour.) Kudô & Masam. was active against B. cereus with the MIC of 1.5 μg/mL (Fukai et al. ref. 2004).

Chromanes and chromenes

Plants in the fabids and malvids produce antibacterial chromanes and chromenes (Figure 19). For instance, cyanomaclurin (230) from Artocarpus heterophyllus Lam. (Moraceae) was bacteriostatic for S. mutans (Septama and Panichayupakaranant ref. 2015). Brasilin (231) from Caesalpinia sappan L. (Fabaceae) used in traditional Chinese medicine was active against MRSA, VRE, and MDR-Burkholderia cepacia (Xu and Lee ref. 2004) as well as S. pyogenes (MIC: 4 µg/mL) (Yin et al. ref. 2004). C. sativa produces cannabichromene (232) (S. aureus, MIC: 2 µg/mL) (Appendino et al. ref. 2008; Radwan et al. ref. 2009). The dimeric prenylated chromane garciniacowol (233) from G. cowa inhibited MRSA with the MIC of 2 µg/mL (Siridechakorn et al. ref. 2012). The chromane glycoside aloesin (234) in the genus Rumex L. (Polygonaceae) was active against M. tuberculosis (MIC: 2.8 µM) (Liang et al. ref. 2010).

Naphthalenols

They are found in the malvids. Examples are torachrysone (235) in Rumex japonicus Houtt. (Polygonaceae) active against MRSA (MIC: 32 µg/mL) (Hatano et al. ref. 1999) and M. tuberculosis (Nishina et al. ref. 1993; Liang et al. ref. 2010), nepodin (236) from Rumex aquaticus L. (Polygonaceae) (Orbán-Gyapai ref. 2017), and hibicuslide C (237) from Hibiscus taiwanensis S.Y. Hu (Malvaceae) (MDR-P. aeruginosa) (Lee, Choi, et al. ref. 2016). In the monocots, Eleutherine bulbosa (Mill.) Urb. (Iridaceae) produces eleubosas A (238) and B (239) (E. coli, MIC: 12.5 µg/mL) (Jiang et al. ref. 2020) (Figure 20).

Phenanthrenes

Internal cyclization of stilbenes forms antibacterial phenanthrenes and biphenanthrenes in monocots (Chapatwala et al. ref. 1981) (Figure 21). Examples are 2,7-dihydroxy-4-methoxyphenanthrene (240) from Dioscorea bulbifera L. (Dioscoreaceae) (Kuete et al. ref. 2012) and blestriacin (241) from B. striata (MRSA, MIC: 2 μg/mL, bactericidal) (Chen et al. ref. 2018). Bletilla striata produces 4,7,7′-trimethoxy-9′,10′-dihydro(1,3′-biphenanthrene)-2,2′,5′-triol (242) (S. aureus, MIC: 8 µg/mL) as well as 4,8,4′,8′-tetramethoxy(1,1′-biphenanthrene)-2,7,2′,7′-tetrol (243) (S. aureus, bactericidal) (4,8,4′,8′-TBT) (Qian et al. ref. 2015). Arundina graminifolia (D. Don) Hochr (Orchidaceae) yields blestiarene A (244) and densiflorol B (245) bacteriostatic for S. aureus and E. coli (Zhang et al. ref. 2022).

Phenylphenalenones

Diarylheptanoids serve in the monocots as precursors for the synthesis of phenylphenalenones phytoalexins, such as anigorufone (246) from Macropidia fuliginosa (Hook.) Druce (Haemodoraceae) (Brkljaca et al. ref. 2019) (Figure 22). Other antibacterial phenylphenalenones are found in the genus Musa L. (Musaceae) (Krishnamurthy et al. ref. 2023).

Tetralones

Examples are 4-hydroxy-1-tetralone (247) from E. roxburghiana (M. tuberculosis, MIC: 4 µg/mL) (Lin et al. ref. 2005; Wu et al. ref. 2012), l-epineo-isoshinanolone (248) (E. coli, MIC: 12.5 µg/mL), and neoiso-shinanolone (249) from Plumbago zeylanica L. (Plumbaginaceae, malvids) (Jetty et al. ref. 2010) (Figure 23).

Other non-flavonoids

They mostly occur in fabids (Figure 24). Examples are licocoumarone (250) (S. aureus, MIC: 6.2 µg/mL) from G. glabra (Demizu et al. ref. 1988), gancaonin I (251) (MRSA, MIC: 1.5 µg/mL) from Glycyrrhiza uralensis Fisch. ex DC. (Fabaceae) (Fukai et al. ref. 2002), and albanol B (252) from Morus alba L. (Moraceae) (S. typhimurium, MIC: 5 µg/mL) (Park et al. ref. 2003, Sohn et al. ref. 2004).

In the family Hypericaceae, examples are hypatulin A (253) from Hypericum patulum Thunb. (B. subtilis, MIC: 16 μg/mL) (Tanaka et al. ref. 2016), hyperenone A (254) from H. acmosepalum (S. aureus expressing NorA, MIC: 2 µg/mL) (Osman et al. ref. 2012), and hypericin (255) from Hypericum perforatum L. (Feyzioğlu et al. ref. 2013).

Δ₉-Tetrahydrocannabinol (256) and cannabinol (257) from C. sativa are formed via the polyketide pathway (Abe ref. 2020) and were very strongly active against S. aureus (MIC: 1 µg/mL) (Appendino et al. ref. 2008; Radwan et al. ref. 2009). We can also cite harpulliaside A (258) from Harpullia pendula Planch. ex F. Muell. (Sapindaceae) (V. parahaemolyticus, MIC: 35 µg/mL) (Abdelkader et al. ref. 2016) as well as aloin A (259) from A. vera (Coopoosamy and Magwa ref. 2006b).

Flavonoids

Chalcones

The addition of one hydroxycinnamic acid unit with three malonyl-CoA units forms chalcones (Abe et al. ref. 2006; Wang et al. ref. 2023) (Figure 25). These 1,3-diphenyl-2-propen-1-ones occur in the fabids and malvids and are active against Gram-positive bacteria and mycobacteria. Examples are 2′,4′-dihydroxychalcone (260) from Muntingia calabura L. (Mutingiaceae, malvids) bactericidal for S. aureus (MIC/MBC: 50/100 µg/mL) (Sufian et al. ref. 2013) and butein (261) from Butea monosperma (Lam.) Taub. (Fabaceae) (M. tuberculosis, MIC: 12.5 µg/mL) (Chokchaisiri et al. ref. 2009).

The prenylation of chalcones in the family Fabaceae enhances their antibacterial activity as in licochalcone A (262) from Glycyrrhiza inflata Batalin with S. aureus (MIC: 3 µg/mL) (Tsukiyama et al. ref. 2002), MRSA (MIC: 6.2 µg/mL), and P. gingivalis (MIC: 10 µg/mL) (Fukai et al. ref. 2002). Other examples are licochalcone C (263) (M. luteus, MIC: 6.2 µg/mL) (Haraguchi et al. ref. 1998) and isobavachalcone (264) from P. corylifolia (Yin et al. ref. 2004). Sophora flavescens Aiton is used in traditional Chinese medicine and produces 7,9,2′,4′-tetrahydroxy-8-isopentenyl-5-methoxychalcone (7,9,2′,4′-TIMC) (265) which was effective against MRSA (MIC: 0.9 µg/mL) and VRE (MIC: 7.8 µg/mL) (Lee, Kim, et al. ref. 2010).

The condensation of one dihydrohydroxycinnamic acid unit with three malonyl-CoA units forms antibacterial dihydrochalcones (Ibdah et al. ref. 2017) such as phloretin (266) from Malus domestica (Suckow) Borkh. (Rosaceae, fabids) (S. aureus, MIC: 7.8 µg/mL) (Barreca et al. ref. 2014).

Flavanones

Simple flavanones

These antibacterial 2-phenyl-2,3-dihydro-4H-chromen-4-ones come from the cyclization of chalcones in malvids and fabids (Shah and Smith ref. 2020) (Figure 26). Examples are artocarpanone (267) from A. heterophyllus bactericidal for E. coli (MIC/MBC: 3.9/7.8 µg/mL) (Septama and Panichayupakaranant ref. 2017), pinocembrin (268) from G. glabra (M. tuberculosis, MIC: 3.3 µg/mL) (Fukui et al. ref. 1988; Chou et al. ref. 2011), and naringenin (269) in the genus Citrus L. (Rutaceae) (S. pyogenes, MIC: 50 µg/mL) (Macé et al. ref. 2017).

Glycosylation of naringenin (269) in position 8 forms prurin (270) in Acacia farnesiana Wall. (Fabaceae) active against MDR-M. tuberculosis (MIC: 50 µg/mL) and C. jejuni (MIC: 50 µg/mL) (Hernández-García et al. ref. 2019).

Prenylated flavanones

Plants of the Fabaceae family produce prenylated flavanones active against Gram-positive bacteria (Figure 26). Examples of flavanones with dimethylallyl moieties are bavachinin (271) from P. corylifolia (Yin et al. ref. 2004) and licoflavanone (272) in G. glabra (Fukui et al. ref. 1988). From this plant, glabrol (273) and 3-hydroxyglabrol (274) yielded the MIC values of 1.5 and 6.2 µg/mL against S. aureus, respectively (Mitscher et al. ref. 1980). Glabrol (273) was active against M. smegmatis (MIC: 1.5 µg/mL) (Mitscher et al. ref. 1980). Other instances are kurarinone (275) from S. flavescens (MRSA, MIC: 2 µg/mL) (Chen et al. ref. 2005), lupinifolin (276) from Derris reticulata Craib. (Mazimba et al. ref. 2012) (S. aureus, MIC: 8 µg/mL, bactericidal) (Yusook et al. ref. 2017), and euchrestaflavanone A (277) from Flemingia strobilifera (L.) W.T. Aiton (P. aeruginosa, MIC: 17 µg/mL) (Madan et al. ref. 2008).

An example of geranylated flavanone is sophoraflavanone D (278) from Echinosophora koreensis Nakai (Fabaceae) (E. coli MIC: 20 µg/mL) (Sohn et al. ref. 2004). A lavandulyl group enhances the antibacterial strength of flavanones as in sophoraflavanone G (279) from Sophora exigua Craib. (Fabaceae) with a MIC as low as 0.5 µg/mL against MRSA (Cha et al. ref. 2007, ref. 2009).

Plants of the Celastraceae family (fabids) produce antibacterial flavanones. Examples are (2S)-5,7,4′-trihydroxy-2′-methoxy-8,5′-di(3-methyl-2-butenyl)-6-methylflavanone (280) and (±)-5,4′-dihydroxy-2′-methoxy-6′,6″-dimethypyraro-(2″,3″:7,8)-6-methyflavanone (281) (MRSA, IC₅₀: 2 µg/mL) from Tripterygium wilfordii Hook.f. used in traditional Chinese medicine (Chen et al. ref. 2017).

Flavanone-O-glycosides

Taxifolin-7-O-rhamnoside (282) from H. japonicum was bactericidal for MRSA (MIC/MBC: 32/64 µg/mL) (An et al. ref. 2011).

Miscellaneous

There are flavones with complex polyphenolic structures, such as sanggenon D (283) from Morus alba L. (Moraceae) active against S. epidermidis (MIC: 40 µg/mL) (Sohn et al. ref. 2004).

Isoflavans

Plants of the Fabaceae produce antibacterial isoflavans (Pičmanová et al. ref. 2013) (Figure 27). Glabridin (284) from G. glabra inhibited the growth of S. aureus (MIC: 6.2 µg/mL) (Gupta et al. ref. 2008), MRSA (MIC: 12.5 µg/mL) (Fukai et al. ref. 2002), M. smegmatis (6.2 µg/mL) (Mitscher et al. ref. 1980), and P. gingivalis (MIC: 10 µg/mL) (Azelmat et al. ref. 2015). From G. glabra, other antibacterial isoflavans are 3′-methoxyglabridin (285), 4′-O-methylglabridin (286), phaseollinisoflavan (287), hispaglabridin A (288) (S. aureus, MIC: 3.1 µg/mL), and hispaglabridin B (289) (S. aureus, MIC: 6.2 µg/mL) (Mitscher et al. ref. 1980). Other examples include licoricidin (290) (MRSA, MIC: 3.1 µg/mL), glyasperin C (291) (E. faecium), and glyasperin D (292) (MRSA, MIC: 6.2 µg/mL) from G. uralensis (Fukai et al. ref. 2002; Gafner et al. ref. 2011; Eerdunbayaer et al. ref. 2014; Villinski et al. ref. 2014).

Isoflavanones

Plants of the Fabaceae family isomerize flavanones into isoflavanones active against Gram-positive bacteria (Pičmanová et al. ref. 2013). For example, Erythrina variegata L. (Fabaceae) produces orientanol F (293) (MRSA, MIC₉₀: 12.5 µg/mL) (Tanaka et al. ref. 2002), orientanol E (294) (MRSA, MIC₉₀/MBC₉₀: 3.1/25 µg/mL, bacteriostatic) (Tanaka et al. ref. 2015), and bidwillon B (295) (MRSA, MIC: 3.1 µg/mL) (Sato et al. ref. 2003) (Figure 28).

Flavones

Simple flavones

The formation of a Δ^2,3 double bond in flavanones forms flavones that generally have moderate antibacterial activities (Figure 29) (Zhao et al. ref. 2016). Flavones that have an unsubstituted C ring are common in upper Angiosperms. This is the case, for example, of chrysin (297) of Oroxylum indicum (L.) Kurz (Bignoniaceae, lamiids) (Ali et al. ref. 1998; Zhao et al. ref. 2022) and baicalein (298) (S. typhimurium, MIC: 64 μg/mL) in Scutellaria baicalensis Georgi (Lamiaceae, lamiids) used in traditional Chinese medicine (Yang et al. ref. 2000; Wu et al. ref. 2018). Another example is galangin (299) from Helichrysum aureonitens Sch. Bip. (Asteraceae, campanulids) which was active against 4-quinolone-resistant S. aureus (Cushnie and Lamb ref. 2006) and Mycobacterium phlei (MIC: 50 µg/mL) (Pomilio et al. ref. 1992).

Flavones with hydroxylated C rings are ubiquitous in Angiosperms and include notably apigenin (300) (K. pneumoniae, MIC: 25 µg/mL), luteolin (301) (P. aeruginosa, MIC: 25 µg/mL) (Sathiamoorthy et al. ref. 2007; Bustos et al. ref. 2018), kaempferol (302) (S. mutans, MIC: 32 µg/mL) (Yamada et al. ref. 1999), quercetin (303) (Salmonella enteridis, MIC: 15.6 µg/mL) (Phadungkit and Luanratana ref. 2006), robinetin (304) (Mori et al. ref. 1987), and myricetin (305) (Xu et al. ref. 2015).

Methoxylated flavones

Upper Angiosperms often produce antibacterial methoxylated flavones (Figure 29). We can cite for instance isorhamnetin (306) from A. elliptica (S. typhimurium, MIC: 15.6 µg/mL) (Phadungkit and Luanratana ref. 2006). Vitex negundo L. (Verbenaceae) produces penduletin (307) (MRSA, MIC: 10 µg/mL) (Sichaem et al. ref. 2021) and artemetin (308) (K. pneumoniae, MIC: 25 µg/mL) (Sathiamoorthy et al. ref. 2007). Other examples are found in the family Asteraceae (Murillo et al. ref. 2003).

Prenylated flavones

They are common in the family Moraceae and include papyriflavonol A (309) from Broussonetia papyrifera (L.) L’Hér. ex Vent. (S. typhimurium, MIC: 10 µg/mL), morusin (310) from Morus mongolica (Bureau) C.K. Schneid. (S. epidermidis, MIC: 20 µg/mL), kuwanon C (311) (S. typhimurium, MIC: 6.2 µg/mL) (Sohn et al. ref. 2004), kuwanon G (312) (S. mutans, MIC: 8 µg/mL) from M. alba (Park et al. ref. 2003), and artocarpin (313) from A. heterophyllus (S. mutans, MIC/MBC: 4.4/8.9 µM) (Septama and Panichayupakaranant ref. 2018) (Figure 29).

Flavone-O-glycosides

Examples are isocytisoside (314) from Aquilegia vulgaris L. (Ranunculaceae) (S. aureus, MIC: 15.6 µg/mL) (Bylka et al. ref. 2004), quercetin 7-O-glucoside (315) in Gossypium arboreum L. (Malvaceae) (Waage and Hedin ref. 1984) (Figure 29). Other illustrations are afzelin (316) and kaempferol-7-rhamnoside (317) from Bryophyllum pinnatum (Lam.) Oken (Crassulaceae, core eudicots) active against S. typhi with the MIC values of 2 and 1 µg/mL, respectively (Tatsimo et al. ref. 2012), luteoloside (318) from L. japonica (Xiong et al. ref. 2013), hyperoside (319) from H. perforatum (Pretorius et al. ref. 2003; Saçıcı and Yesilada ref. 2022), as well as taxifolin-7-O-α-l-rhamnopyranoside (320) (TLRP) (An et al. ref. 2011). Baicalin (321) from S. baicalensis inhibited the growth of S. typhimurium (MIC/MBC: 64/>128 μg/mL) (Wu et al. ref. 2018). Rutin (322) from Sophora japonica L. (Fabaceae) (Balbaa et al. ref. 1974) was active P. aeruginosa, A. baumannii, and S. aureus with the MIC values of 16, 8, and 4 µg/mL, respectively (Orhan et al. ref. 2010).

Flavone-C-glycosides

Apigenin-8-C-glucopyranoside (vitexin) (323) (Figure 29) from V. negundo inhibited the growth of Mycobacterium fortuitum (MIC: 30 µg/mL) (Aderogba et al. ref. 2019). It should be noted that vitexin (323), although weakly active in vitro against S. aureus, was nevertheless active in vivo against S. aureus with an additional inflammatory action (Das et al. ref. 2022).

Isoflavones

The isomerization and dehydrogenation of flavanones form isoflavones in the family Fabaceae (Artigot et al. ref. 2013) (Figure 30). These phytoalexins are often active against Gram-positive bacteria and include for instance biochanin A (324) from Cassia fistula L. (Sartorelli et al. ref. 2009) (S. pyogenes, MIC: 32 µg/mL) (Pohjala et al. ref. 2012; Hummelova et al. ref. 2015), santal (325) from Derris scandens (Roxb.) Benth. (MRSA, MIC: 2 µg/mL) (Mahabusarakam et al. ref. 2004), and formononetin (326) from Glycyrrhiza pallidiflora Maxim. (Kajiyama et al. ref. 1993; Mutai et al. ref. 2015). In the family Iridaceae (monocots), tectorigenin (327) from Belamcanda chinensis (L.) Redouté was active against S. aureus (MIC: 50 µg/mL) (Oh et al. ref. 2001) and MRSA (MIC: 125 µg/mL) (Joung et al. ref. 2014).

Prenylated isoflavones

They are prevalent in the Fabaceae family and are active against Gram-positive bacteria (Figure 30). Examples are licoisoflavone A (328) and B (329) from G. uralensis (MRSA, MIC: 32 µg/mL) (Wu et al. ref. 2019; Chen et al. ref. 2023), derrisisoflavone A (330) from D. scandens (MRSA, MIC: 4 µg/mL) (Mahabusarakam et al. ref. 2004), lupalbigenin (331) from G. dulcis (S. aureus, MIC: 4 µg/mL) (Deachathai et al. ref. 2005), 6,8-diisoprenyl-5,7,4′-trihydroxyisoflavone (332) (S. mutans, MIC: 2 µg/mL) (He et al. ref. 2006), 8-(γ,γ-dimethylallyl)-wighteone (333) from G. uralensis (MRSA, MIC: 8 µg/mL) (Hatano et al. ref. 2000; Eerdunbayaer et al. ref. 2014), and auriculasin (334) from Flemingia philippinensis Merr. & Rolfe with MDR-E. coli (MIC: 2 µg/mL) (Mohamed et al. ref. 2022).

Isoflavone glycosides

Genistin (335) from F. strobilifera inhibited the growth of S. epidermidis, S. aureus, MRSA, P. aeruginosa, and E. coli with the MIC of 31.2, 62.5, 34, 125, and 146 µg/mL, respectively (Madan et al. ref. 2008; Boutaghane et al. ref. 2019) (Figure 30).

Pterocarpans

The reduction and cyclization of isoflavones form pterocarpans in the family Fabaceae. These phytoalexins are strongly active against Gram-positive bacteria (Figure 30). Examples are glycinol (336) from Glycine max (L.) Merr. (Weinstein and Albersheim ref. 1983), orientanol C (337) from E. variegata (MRSA, MIC₉₀:12.5 µg/mL), as well as orientanol B (338) (MIC: 3.1 µg/mL) (Tanaka et al. ref. 2002). From this plant, erycristagallin (339) was active against MRSA (MIC₉₀: 6.2 µg/mL) (Tanaka et al. ref. 2002) and Actinomyces viscosum (MIC: 1.5 µg/mL) (Sato et al. ref. 2003). Glycyrrhizol A (340) and B (341) from G. uralensis inhibited S. mutans with the MIC values of 1 and 32 µg/mL, respectively (He et al. ref. 2006). Erybraedin A (342) from E. zeyheri was bacterostatic for VRE (MIC: 1.5 µg/mL) (Sato et al. ref. 2004).

Flavans

The reduction of flavanones forms antibacterial flavans (Cao et al. ref. 2020) (Figure 31). Examples are catechin (343) gallocatechin (344) (Pretorius et al. ref. 2003), and epigallocatechin (345) (M. smegmatis, MIC: 7.8 µg/mL) (Mativandlela et al. ref. 2007). (−)-Epigallocatechin 3-O-gallate (EGCG) (346) from Camellia sinensis (L.) Kuntze (Theaceae, asterids) inhibited the growth of C. jejuni (MIC: 8 μg/mL), N. gonorrhoea (MIC: 32 μg/mL), S. pneumoniae (MIC: 32 μg/mL) (Matsumoto et al. ref. 2012), MDR-A. baumannii (MIC: 78 μg/mL, bactericidal) (Osterburg et al. ref. 2009), and S. maltophilia (Navarro-Martínez et al. ref. 2005; Gordon and Wareham ref. 2010).

Antibacterial strength and spectrum of activity

Over the last decades, several MIC threshold values have been proposed to identify natural plant products with very strong antibacterial activity (Fabry et al. ref. 1998; Ríos and Recio ref. 2005), the latest being a MIC ≤ 4 µg/mL (Tankeo and Kuete ref. 2023). Since phenolic compounds often have low therapeutic indices and limited oral bioavailabilities (Serrano et al. ref. 2009; Velderrain-Rodríguez et al. ref. 2014) we recommend reducing this threshold value below 2 µg/mL.

Thus, out of ∼350 antibacterial phenolic compounds identified from 1945 to 2023 in Angiosperms from Asia and the Pacific, 44 are very strongly active (MIC < 2 µg/mL) (Table 1). To the extent that resistance thresholds must be considered for antibiotics, a MIC of <1 µg/mL could be used as a threshold for the possible clinical development of natural products. Plumbagin (127), isodiospyrin (137), malabaricone A (164), malabaricone B (165), anacardic acid (170), cannabidiol (174), bakuchiol (176), hypercalin B (181), lupulone (183), rhodomyrtone (186), cowanone (191), α-mangostin (201), β-mangostin (202), garcicowanone A (206), 7,9,2′,4′-tetrahydroxy-8-isopentenyl-5-methoxychalcone (265), and sophoraflavanone G (279) have a MIC < 1 µg/mL against Gram-positive bacteria. A MIC of <1 µg/mL was obtained with 1′-acetoxychavicol acetate (21), juglone (124), 3-methoxyjuglone (125), plumbagin (127), and 2-methoxy-7-methyljuglone (128) against mycobacteria. Dendrocoumarin (53) and cannabidiol (174) have a MIC < 1 µg/mL against Gram-negative bacteria.

Distribution of phenolic compounds with very strong antibacterial activity

Among those above 44 phenolic compounds, 33 originate from core Angiosperms, including 25 from fabids (Table 2). In the fabids, eight phenolic compounds come from the Fabaceae family, five from the Clusiaceae family, and three from the Hypericaceae family. The other major clades that produce such compounds are the core Angiosperms are the malvids and that fabids (which are sister groups) and the Asterids Fabids and Malvids produce prenylated phenolic compounds. Asterids produce naphthoquinones. No phenolic compounds with very strong antibacterial activity were identified among protomagnoliids, eudicots, rosids, lamiids, and campanulids.

Influence of molecular mass on the antibacterial strength and spectrum of activity

The molecular mass of phenolic compounds can be tentatively classified as follows: <200 g/mol = low, 200–400 g/mol = moderate, and >400 g/mol = high. Consequently, phenolic compounds with very strong activity against Gram-positive bacteria, Gram-negative bacteria, or mycobacteria have on average a low, moderate, or high molecular mass (Table 1). These phenolic compounds have molecular masses ranging from 174.1 to 518.7 g/mol. None of the phenolic compounds with a MIC < 1 µg/mL against Gram-negative bacteria or mycobacteria have high molecular masses, probably due to porins’ molecular mass exclusion limit (Bauer et al. ref. 1988; Niederweis ref. 2003).

Influence of solubility on the antibacterial strength and spectrum of activity

The solubility of phenolic compounds can be tentatively classified as follows at pH 7.4: LogD <1 = hydrophilic, LogD between 1 and 5 = amphiphilic, and LogD > 5 = lipophilic. Consequently, phenolic compounds with very strong antibacterial activity are on average amphiphilic (Table 1). Phenolic compounds with a MIC < 1 µg/mL against Gram-positive bacteria are lipophilic or nearly lipophilic. Phenolic compounds with a MIC < 1 µg/mL against Gram-negative bacteria are hydrophilic, amphiphilic, or lipophilic. Lipophilic compounds do not pass through the porins of Gram-negative bacteria (Bauer et al. ref. 1988; van den Berg ref. 2010), suggesting a mechanism of action for lipophilic phenolic compounds involving the permeabilization of the outer membrane. Likewise, porins of mycobacteria likely prevent the entry of lipophilic phenolic compounds. The polar surface area of phenolic compounds with very strong antibacterial activity varies from 29 to 166 Ų.

Main mechanisms of action

Most phenolic compounds are bactericidal. Their two main mechanisms of action are the permeabilization of the cytoplasmic membrane and the destruction of the peptidoglycan wall (Table 3). Downstream effects of cytoplasmic membrane permeabilization include respiratory chain inhibition, change in cytoplasmic pH, generation of reactive oxygen species, and ultimately the inhibition of DNA, RNA, and protein synthesis (Booth ref. 1985; Kubo et al. ref. 2003; Yuan et al. ref. 2021). For mycobacteria, the principal mechanism of action is the inhibition of enzymes, such as DNA primase (Gajadeera et al. ref. 2015) or shikimate kinase (Pandey et al. ref. 2016). There does not appear to be a relationship between molecular mass or solubility with a specific bacterial target.

Structure-activity

General observations

Phenolic compounds with a MIC < 2 µg/mL are, for the most part, not flavonoids (Table 1). These mainly include long-chain alkyl phenols, prenylated phloroglucinols, prenylated xanthones, and 1,4-naphthoquinones. Dimethylallyl, geranyl, farnesyl, lavandulyl, and long-chain alkyl groups tend to penetrate and remain in the hydrophobic region of the cytoplasmic membrane and, in doing so, render it permeable (Tsukiyama et al. ref. 2002; Appendino et al. ref. 2008; Kim et al. ref. 2014; Omosa et al. ref. 2016; Araya-Cloutier et al. ref. 2018; Yuan et al. ref. 2021) (Table 3). In addition, when these groups make phenolic compounds amphiphilic, they become surfactants (Xia et al. ref. 1995). Phenolic compounds that cross the porins of Gram-negative bacteria (hydrophilic or close to hydrophilic) reach the cytoplasmic membrane to destabilize it.

This is probably the case for (−)-nortrachelogenin (85) (Lee, Ji, et al. ref. 2016) and glochidioboside (89) with E. coli O157:H7 (Lee, Woo, et al. 2015). A restricted number of freely rotating chemical bonds and the presence of a planar skeleton (as in anthraquinones or naphthoquinones) favor the intercalation of phenolic compounds within bacterial DNA (Table 3) (Bhakta and Siva ref. 2012). Most phenolic compounds with a MIC < 1 µg/mL against mycobacteria are 1,4-naphthoquinones.

Non-flavonoid phenolic compounds

The presence of quinone scaffolds and an increase in hydrogen bond acceptors enhance the activity of non-flavonoid phenolic compounds (Table 1). Quinones, through the redox cycle (Lown ref. 1983) and in the presence of Cu²⁺ and O₂, generate reactive oxygen species that destroy bacterial DNA (Sakihama et al. ref. 2002). This is the case for plumbagin (127) in E. coli (Farr et al. ref. 1985). Naphthoquinones and other planar phenolic compounds with adjacent hydroxyl and ketone groups chelate Zn²⁺ ions and, in doing so, inhibit zinc metalloenzymes, such as topoisomerase I (Tse-Dinh and Beran-Steed ref. 1988; Plyta et al. ref. 1998; Tesauro et al. ref. 2010). Catechol groups in tannins and other polyhydroxylated phenolic compounds chelate Fe³⁺ ions which are necessary for bacterial growth (Serrano et al. ref. 2009; Farha et al. ref. 2020). Similarly, pyrogallol groups chelate divalent cations that are essential for the stabilization of the negative charges in the central oligosaccharide chains of the outer layer of Gram-negative bacteria (Denyer and Maillard ref. 2002; Taguri et al. ref. 2006).

Certain functional groups readily and randomly form cross-links with bacterial macromolecules. For example, furan and pyrone moieties in furanocoumarins form covalent bonds with DNA and proteins (Dall’Acqua et al. ref. 1978; Bordin et al. ref. 1993; Wamer et al. ref. 1995). Similarly, α, β-unsaturated carbonyls in butenolides readily open to form covalent bonds with the nucleophilic groups (thiols) of proteins via hetero-Michael addition reactions (Jackson et al. ref. 2017). Benzoquinones form covalent bonds with proteins (Wipf and Jung ref. 1999; Hettegger et al. ref. 2021). Other examples include α-methylene γ-lactones that alkylate DNA and proteins (Gach and Janecka ref. 2014). Tannins randomly interact with surface proteins and the cytoplasmic membrane (Shimozu et al. ref. 2017; Tintino et al. ref. 2017; Wang et al. ref. 2020) and at high concentrations coagulate proteins (Serrano et al. ref. 2009). Thus, they often behave as invalid metabolic panaceas.

Another mechanism of action is the induction of apoptosis as in pterostilbene (58) with B. cereus (Shih et al. ref. 2021) and quercetin (303) (Li et al. ref. 2015). None of these compounds are known so far to interact with outer membrane protein A (OmpA) in A. baumannii (Nie et al. ref. 2020).

Flavonoids

Prenyl groups enhance the activity of flavonoids against Gram-positive bacteria (Matsumoto et al. ref. 2012; Yuan et al. ref. 2021), as in 7,9,2′,4′-tetrahydroxy-8-isopentenyl-5-methoxychalcone (265) and sophoraflavanone G (279) (Table 1). Sophoraflavanone G (279) is a surfactant that induced the lysis of E. faecium (Tsuchiya and Iinuma ref. 2000; Kim and Kim ref. 2020). Flavonoid glycosides are able to pass through porins and can therefore dissolve the cytoplasmic membrane of Gram-negative bacteria (Tagousop et al. ref. 2018). This could explain why the only flavonoid with a MIC < 2 against a Gram-negative bacterium is kaempferol-7-rhamnoside (317). No flavonoid showed very strong activity against mycobacteria.

Regarding the influence of the number and the position of hydroxyl groups on the antibacterial mechanism of flavonoids, a hydroxyl group at carbon 3 of ring A and hydroxylation of ring B at carbons 3′, 4′, or 5′ promote the intercalation of flavonoids into bacterial DNA (Bartoszewski and Króliczewski ref. 2019). It has also been observed that a hydroxyl group at carbon 3 (Hazni et al. ref. 2008), 5, 6, or 7 enhance antibacterial activity (Hummelova et al. ref. 2015). However, an increasing number of hydroxyl groups results in a decrease in activity (Mori et al. ref. 1987; Xu et al. ref. 2015). Flavonoids with catechol scaffolds or hydroxyl groups at carbon 3 or 5 and a ketone group at position 4 can chelate Fe³⁺ ions (Porfírio et al. ref. 2014; Jahanshahi et al. ref. 2022).

Synergistic activity with antibiotics

Weakening of intrinsic resistance

Phenolic compounds are primarily synergistic with β-lactam antibiotics against Gram-positive bacteria and, to a lesser extent, with aminoglycosides, tetracyclines, and fluoroquinolones (Table 4). There is no obvious association between the molecular mass or solubility of phenolic compounds and synergistic effects with specific classes of antibiotics. However, there appears to be a link between mechanism of action and synergy with a given class of antibiotic. For example, phenolic compounds targeting the cytoplasmic membrane or the peptidoglycan wall often work synergistically with antibiotics targeting the cytoplasmic membrane or the peptidoglycan wall (Table 4). The synergistic mechanism of action phenolic compounds with prenyl or long-chain alkyl groups relies, at least in part, on the destabilization of the cytoplasmic membrane (Tsukiyama et al. ref. 2002; Appendino et al. ref. 2008; Omosa et al. ref. 2016; Zabawa et al. ref. 2016).

Antibiotics whose activity is increased against Gram-negative bacteria in the presence of phenolic products are often those that target the synthesis of ribosomes, DNA, or folic acid metabolism, as well as the lipopolysaccharide envelope. For example, polymyxin B, colistin, and other antibiotics whose functioning is based on the permeabilization of the outer envelope of lipopolysaccharides allow the penetration of phenolic compounds (amphiphilic or lipophilic) previously unable to cross porins. This mechanism could, at least in part, explain the synergy observed between polymyxin B and cajanin stilbene acid (62) in mice against E. coli (Jia et al. ref. 2023) and polymyxin B and cannabidiol (174) against polymyxin B-resistant A. baumannii (Hussein et al. ref. 2022). In addition, pyrogallol form complexes with divalent cations which are essential for the stabilization of the outer lipopolysaccharides coat of Gram-negative bacteria (Denyer and Maillard ref. 2002; Taguri et al. ref. 2006) and thus reduce the resistance of Gram-negative bacteria to antibiotics as in the case of ellagic acid (113) and tannic acid (158) (Andjelković et al. ref. 2006; Jayaraman et al. ref. 2010). Tannins, such as corilagin (159), work synergistically with β-lactam antibiotics against Gram-positive bacteria (Shimizu et al. ref. 2001).

Phenolic compounds are not only synergistic with antibiotics but also among each other. The question then arises as to whether the synergy of phenolic compounds would constitute an additional strategy developed by plants to keep phytopathogenic bacteria in check. For example, rhein (144) is synergistic with licochalcone A (262), glabridin (284), or myricetin (305) against P. gingivalis (Azelmat et al. ref. 2015).

Efflux pumps

Gram-negative bacteria resist antibacterial phenolic compounds by means of efflux pumps (Kuete et al. ref. 2010). Several phenolic compounds inhibit these pumps, such as gallic acid (99) and ellagic acid (113) with TetK in S. aureus (Macêdo et al. ref. 2022), juglone (124) (Zmantar et al. ref. 2016), and tannic acid (158) (Tintino et al. ref. 2017). Ellagic acid (113) and tannic acid (158) inhibited efflux pumps in A. baumannii (Chusri et al. ref. 2009). It appears that prenyl groups particularly farnesyl and lavandulyl groups, can bind to and inhibit voltage-gated Ca²⁺ channels (De Loof and Schoofs ref. 2019). The resulting decrease in the concentration of Ca²⁺ ions in the cytoplasm leads to the inhibition of Ca²⁺-dependent efflux pumps (Nava et al. ref. 2020). This mechanism likely explains why sophoraflavanone G (279) inhibited NorA in MRSA (Sun et al. ref. 2020). Some molecules used therapeutically that act on human neuroreceptors, such as reserpine are in vitro capable to inhibit bacterial efflux pumps (Piddock et al. ref. 2010; Sridevi et al. ref. 2017; Saber and Kandala ref. 2018). It raises the question of whether neuroactive phenolic products would be a potential group of pump inhibitors.

β-Lactamases

Benzoic acid derivatives (Jiamboonsri et al. ref. 2023), proanthocyanidin oligomers (Kusuda et al. ref. 2006), and flavones tend to inhibit β-lactamases (Siriwong et al. ref. 2015).

Escaping the development resistance

Antibacterial phenolic compounds that target the cytoplasmic membrane of Gram-positive bacteria evade bacterial resistance. This the case for instance of brasilin (231) with MRSA (Xu and Lee ref. 2004), sophoraflavanone G (279) with MRSA (Weng et al. ref. 2023), blestriacin (241) with S. aureus (Chen et al. ref. 2018), malabaricone B (165) with S. aureus (Sivadas et al. ref. 2023), glabrol (273) with MRSA (Wu et al. ref. 2019), as well as cannabidiol (174) with MRSA (Blaskovich et al. ref. 2021).

Toxicity

Unlike traditional antibiotics which come from bacteria or fungi, phenolic compounds from Angiosperms have the advantage of not having specific bacterial targets. It allows them to avoid the development of resistance but gives them a generally narrow therapeutic window. Most phenolic compounds have the disadvantage of often being toxic in vitro for mammalian cells at concentrations close to or similar to their MICs. This is the case for xanthones (Boonsri et al. ref. 2006; Mahabusarakam et al. ref. 2008; Yahayu et al. ref. 2013; Pattamadilok ref. 2016), lignans (Syu et al. ref. 2004; Manna et al. ref. 2015), naphthoquinones (Gu et al. ref. 2004; Yang et al. ref. 2019), coumarins (Phatchana and Yenjai ref. 2014), stilbene oligomers (Sahidin et al. ref. 2017), prenylated flavonoids (Sohn et al. ref. 2004), phenolic glycosides (Zeng et al. ref. 2015), and anthraquinones (Ali et al. ref. 2000). Planar phenolic compounds, such as anthraquinones can intercalate into DNA, inhibit topoisomerase II, and induce chromosomal damage in mammalian cells (Mueller and Stopper ref. 1999; Bhakta and Siva ref. 2012; Chakarov et al. ref. 2014). Examples of pan-assay interference compounds (PAINS) or invalid metabolic panacea (IMP) are curcumin (75) and tannins (Bisson et al. ref. 2016; Nelson et al. ref. 2017). It is therefore necessary to determine the selectivity indices of antibacterial phenolic compounds. An antibacterial phenolic compound with a selectivity index >10 merits further pharmacological examination (Tamargo et al. ref. 2015). This is the case for 2-methoxy-7-methyljuglone (128) (Gu et al. ref. 2004), maritinone (132), 3,3′-biplumbagin (135) (Uc-Cachón et al. ref. 2014), malabaricone A (164) (Orabi et al. ref. 1991), and malabaricone B (165) (Sivadas et al. ref. 2023). Phenolic products with unfavorable selectivity indexes can be used to synthesize less toxic antibacterial derivatives (Cham et al. ref. 2023).

Clinical potential

Several phenolic compounds identified in Asian and Pacific Angiosperms can combat bacterial infections in vivo. For example, ethyl gallate (100) administered orally at a dose of 50 mg/kg/day increased the survival rate of mice infected with S. typhimurium by more than 70% (Choi et al. ref. 2014). Anacardic acid (170) and glabrol (273) were active against MRSA and VRE in insects, respectively (Wu et al. ref. 2019; Saedtler et al. ref. 2020). Furthermore, a very interesting aspect of phenolic compounds pharmacology is that they can be both antibacterial and anti-inflammatory or even immunomodulatory. The inflammatory response during infections caused by Gram-negative bacteria is owed, at least in part, by lipopolysaccharides which induce the secretion of nitric oxide and cytokines. Antibacterial phenolic compounds like euryacoumarin A (30) inhibit lipopolysaccharide-induced nitric oxide production in RAW264.7 (IC₅₀: 35.6 μM) (Song et al. ref. 2017). Vitexin (323) given at the dose of 400 µg/kg inhibited lipopolysaccharides-induced lung inflammation in mice (De Melo et al. ref. 2005). Vitexin (323) given parenterally at the dose of 60 mg/kg to mice infected with S. aureus attenuated the production of pro-inflammatory cytokines (Chen et al. ref. 2022). Baicalin (321) was able to protect mice against S. typhimurium infection, modulate bacterial virulence, and quell the host inflammatory response (Wu et al. ref. 2018). Another example is [6]-gingerol (167) which exerted both antibacterial and immunomodulatory activity against M. tuberculosis in mice (Bhaskar et al. ref. 2020).

Concerning the synergistic effect of antibacterial phenolic compounds with antibiotics in vivo, examples are chlorogenic acid (4) with levofloxacin against K. pneumoniae (Tan, Gao, et al. ref. 2020), plumbagin (127) with colistin against colistin-resistant P. aeruginosa (Wang, Kong, et al. ref. 2022), and sophoraflavanone G (279) with norfloxacin against effluxing antibiotic-resistant S. aureus (Sun et al. ref. 2020). Baicalein (298) was synergistic with ampicillin against Streptococcus suis (Lu et al. ref. 2021), with linezolid against S. aureus (Liu et al. ref. 2020), and with myricetin (305) with oxacillin against MRSA (Pinto et al. ref. 2020).

Concluding remarks

The knowledge accumulated over the last decades highlights that the phenolic compounds with very strong antibacterial activity identified in the Angiosperms of Asia and the Pacific mainly come from fabids, often carry isoprene or long-chain alkyl groups, are often planar, with a molecular mass ranging from ∼200 to 400 g/mol, and are often amphiphilic. These products are mainly active against Gram-positive bacteria, and primarily target the cytoplasmic membrane, thus avoiding the development of resistance. 2-Methoxy-7-methyljuglone (128), malabaricone A (164), and malabaricone B (165) (Sivadas et al. ref. 2023) with MIC values <1 µg/mL and selectivity indices >10 could potentially be developed as antibacterial agents as well as anacardic acid (170). Unlike commonly used antibiotics, some of these phenolic compounds are not only antibacterial or antibiotic potentiators but also anti-inflammatory or immunomodulators, such as [6]-gingerol (167), baicalin (321), and vitexin (323). The clinical development of antibiotics or antibiotic potentiators to treat pan-resistant bacteria from phenolic compounds from Asia and Pacific Angiosperms should come to light.

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