Structure-dependent activity of plant natural products against methicillin-resistant Staphylococcus aureus

Frontiers in Microbiology 01 frontiersin.org Structure-dependent activity of plant natural products against methicillin-resistant Staphylococcus aureus CalistoMoreno Cardenas and SerhatS.Çiçek * Department of Pharmaceutical Biology, Institute of Pharmacy, Kiel University, Kiel, Germany Methicillin-resistant Staphylococcus aureus (MRSA) is one of the major causes for nosocomial infections and has been classified as “high priority pathogen” by the World Health Organization. Its ability to develop resistances has been a challenge for the last decades and is still a threat to health care systems, as strains with resistances to the so-called drugs of last resort have been discovered. Therefore, new antibiotics are urgently needed. Natural products are an important source for the development of new drugs, thereby mostly serving as lead compounds for further modification. In this review, the data on plant natural products with reported anti-MRSA activity until the end of 2022 is discussed, highlighting the most effective drugs with respect to their inhibitory concentrations as well as with regard to eventual synergistic effects with existing antibiotics. In the latter sense, the class of alkaloids must bementioned, exhibiting additive or synergistic effects by inhibiting bacterial efflux pumps. With regard to the antibiotic activity, phloroglucinol derivatives certainly belong to the most promising compounds, revealing several candidates with remarkable effects, e.g., lupulone, ivesinol, rhodomyrtone, aspidinol, or hyperforin. Also, the class of terpenoids yielded noteworthy compounds, such as the sesquiterpene lactones parthenolide and lactopicrin as well as acetophenone sesquiterpenes and sphaerodiene type diterpenoids, respectively. In addition, pronounced effects were observed for the macrolide neurymenolide A and three flavonol dicoumaroylrhamnosides. KEYWORDS MRSA, natural product, antimicrobial resistance, antibiotic, phloroglucinol, sesquiterpenoid, diterpenoid, macrolide 1. Introduction Due to the increasing age of the population, especially in industrialized nations, hospital or nursing home-acquired infections are becoming a major problem (Hasanpour etal., 2023). Antimicrobial resistance is prognosed to cause 10 million annual deaths by the year 2050, rendering it the second leading cause of death after cardiovascular diseases (Nandhini etal., 2022). Many of these infections are associated with methicillin-resistant Staphylococcus aureus (MRSA), which has a mortality rate of around 14% in patients with drug-resistant infections in the US (CDC, 2013). However, the prevalence of healthcare-associated MRSA varies for different countries, with, e.g., Portugal (58.4%), Pakistan (52%), India (46%), China (45%), and Norway (38.9%) showing high ratios, while other countries such as Mexico (19.1%), Australia (15.1%), and Germany (4.6%) are much less affected (Shoaib et al., 2022). Even though the first observation of resistance dates back to the 1960s (Jevons, 1961), MRSA is still a threat to OPEN ACCESS EDITED BY Guangtao Zhang, Binzhou Medical University, China REVIEWED BY Clarissa Sit, Saint Mary's University, Canada Ritesh Raju, Western Sydney University, Australia Chunshuai Huang, Shanghai Institute of Materia Medica (CAS), China *CORRESPONDENCE Serhat S. Çiçek [email protected] RECEIVED 03 June 2023 ACCEPTED 14 July 2023 PUBLISHED 15 August 2023 CITATION Moreno Cardenas C and Çiçek SS (2023) Structure-dependent activity of plant natural products against methicillin-resistant Staphylococcus aureus. Front. Microbiol. 14:1234115. doi: 10.3389/fmicb.2023.1234115 COPYRIGHT © 2023 Moreno Cardenas and Çiçek. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. TYPE Review PUBLISHED 15 August 2023 DOI 10.3389/fmicb.2023.1234115 Moreno Cardenas and Çiçek 10.3389/fmicb.2023.1234115 Frontiers in Microbiology 02 frontiersin.org health-care systems, evolving more and more resistance mechanisms against a broad spectrum of antibiotics. Apart from communityassociated MRSA strains, livestock-associated strains also serve as a reservoir for resistance (Cuny et al., 2013). In 2017, MRSA was classified as a “high priority pathogen” by the world health organization (WHO, 2017), stating the urgent need to develop new treatments against this bacterium, i.e., new substances with antibiotic or antibiofilm activity. MRSA causes different kinds of infections including bacteremia, skin and soft-tissue infections, infective endocarditis, osteoarticular infections, pleuropulmonary infections, and many more (Tong etal., 2015). This often leads to complications or prolongation of clinical treatments. In the European Union, MRSA causes the second most infections of any drug-resistant pathogen, only surpassed by the cephalosporin-resistant Escherichia coli (ECDC, 2021). The treatment includes antibiotics of the so-called drugs of last resort (DoLR) like vancomycin, daptomycin, linezolid, and tigecycline (Choo and Chambers, 2016; Subramani etal., 2017). Alarmingly, strains with resistance to one of these antibiotics have already been detected (Layer etal., 2021). An overriding cause for the development of microbial resistance is the misuse of antibiotics (Abreu etal., 2012; Peacock and Paterson, 2015; Rossiter etal., 2017). Most resistance mechanisms affect the uptake and efflux of the antibiotic, alter the target structure, modify the antibiotic, or even produce enzymes to inactivate the antibiotic (Peacock and Paterson, 2015; Rossiter etal., 2017). If a strain adopts a resistance the respective gene can bepassed along through division or horizontal gene transfer (Peacock and Paterson, 2015; ÁlvarezMartínez etal., 2020). Because most of the available antibiotics against MRSA target the cell wall biosynthesis, new lead compounds with other bacteriostatic or bactericidal mechanisms are urgently needed (Choo and Chambers, 2016). In the past, several natural products have led to effective antibiotics, such as penicillin and vancomycin, with, however, a greater focus on fungal or bacteria-derived compounds (Katz and Baltz, 2016; Wright, 2017; Porras etal., 2021). Nevertheless, plants are a rich source of diverse lead compounds, such as alkaloids, terpenoids, quinones, or polyphenols. These substances protect organisms against harmful bacteria, fungi, and insects, thereby offering greater structural variety than standard small molecule libraries (Subramani etal., 2017; Zaynab etal., 2018; Atanasov etal., 2021). Considering the fact that no new antibiotic class has been approved by the FDA since the late 1980s, the broad diversity of specialized plant metabolites may contribute to the development of future antimicrobials (Durand etal., 2019). The traditional use of medicinal plant species against numerous kinds of infectious diseases is a good starting point for the exploration of new antibiotic lead structures (Anand et al., 2019; Porras et al., 2021). Some plant extracts are already used for the treatment of skin infections caused by MRSA, such as the essential oil from the tea tree Melaleuca alternifolia (Myrtaceae) (Nandhini etal., 2022). In addition, not only the pure antibiotic effect is of interest, but also potential additive or synergistic effects with existing antibiotics might bean approach against adapted resistances (Sadeer and Mahomoodally, 2021). In the following, 223 natural products from various plant species are discussed with regard to their structure and antibacterial effects against 169 different MRSA strains (Supplementary Table S1) as well as for their synergistic effects with a range of different antibiotics. 2. Methods A literature search was carried out using the Web of Science citation index, including all publications published until the end of 2022. The search terms “MRSA” and “natural products” were used yielding 833 results. These were reduced to the field of plant science resulting in 148 hits. Also, other sources were collected, which were not found by database search with the previous terms, yielding a total of 223 plant natural products with reported anti-MRSA activity. The compounds were sorted by compound class, thereby taking compound names and configurations “as is” from the original publications. Plants species names were checked using the “World Flora Online” and eventually changed into the accepted taxa. MIC/IC50 values are given in μg/mL using the number of digits given in the original publications. Values found μmol/mL were converted to μg/mL. Values above 100 μg/mL were considered inactive and thus excluded from the review. Activities above 50 μg/mL were referred to as low, MIC and IC50 values from 10 to 50 μg/mL as moderate and values below 10 μg/ mL as high. For synergistic effects factorial inhibitory concentration index (FICI) values above 2 indicate antagonism, values of 2 to 1 indifference, values of 0.5 to 1 additive effects, and values below 0.5 synergism. The values given in μg/mL represent the MIC of the combination. 3. Results and discussion 3.1. Alkaloids The first compound class to bediscussed in this review is the class of alkaloids, which are a rich source for analgetic or cytostatic drugs, but are rather rare in the field of antibiotics. However, they acted as lead substances in the development of quinolones, thus remaining important scaffolds in drug development (Cushnie etal., 2014). Our literature search revealed most reports for isoquinolines-type alkaloids with a total of eight compounds. Additionally, two lycorine derivatives, two pyrolin-2-on derivatives, two phenanthridine-type alkaloids, one quinolone, and one pyridine-derivative were reported (Figure1). Couroupita guianensis, which is used in traditional South American medicine, yielded 1, a compound with a low MIC value but also low toxicity (Costa etal., 2017). Liu etal. (2021) extracted two isoquinolines (2 and 3) from Doryphora aromatica leaves, with activities ranging from 9.9 to 39.6 μg/mL (2) and from 19.7 to 39.4 μg/ mL (3), respectively. Both compounds were first tested against methicillin-sensitive Staphylococcus aureus and showed higher activity against the resistant clinical isolates. Another two isoquinolines (4 and 5) were isolated from the roots of Zanthoxylum nitidum by Zeng etal. (2022). Compound 4 showed moderate and compound 5 showed low activity against MRSA, but both exhibited pronounced synergistic effects with ampicillin, which were attributed to the inhibition of the bacterial efflux pump. Compound 4 was, furthermore, found to successfully disturb the bacterial biofilm. Compound 6, a quinolone derivative was isolated from Zanthoxylum schreberi, formerly named Zanthoxylum monophylum, and displayed an IC 50 value of 1.5 μg/mL, which was rather low compared to the positive control ciprofloxacin (IC 50 of 0.06 μg/mL) (RodríguezGuzmán et al., 2010). Zuo et al. (2011) isolated two Moreno Cardenas and Çiçek 10.3389/fmicb.2023.1234115 Frontiers in Microbiology 03 frontiersin.org bisbenzylisoquinoline alkaloids (7 and 8) from Stephania tetrandra, a traditional drug in Chinese medicine, with both compounds showing low activity. Yu etal. (2005) and Zuo etal. (2012) both studied compound 9, an isoquinoline alkaloid from Coptis chinensis against different clinical isolates resulting in low to moderate antibacterial effects. However, the compound was found to prevent the bacterium from adhesion and invasion into human gingival fibroblasts, thus also affecting the virulence of MRSA. Additionally, Zuo etal. (2012) isolated 10, from Coptis chinensis, showing a slightly higher activity than 9. Moreover, 9 and 10 showed synergistic effects with different antibiotics. Also here, the synergistic effect was attributed to the inhibition of the bacterial efflux pump. Yu etal. (2019) tested 11 against an MRSA strain that overexpressed the NorA multidrug efflux pump, thus giving inferences for many wildtypeMRSA strains. While 11 was only slightly active when tested alone, a combination with norfloxacin or reserpine led to an eightfold increase in the antibiotic activity. Therefore, 11 was assumed an efflux pump inhibitor and suggested to befurther investigated. The two lycorine derivatives 12 and 13 were isolated from Crinum ornatum, formerly referred to as Crinum distichum, by Koagne etal. (2018) and showed moderate activity. Two sesquiterpene alkaloids (14 and 15) were isolated from the semi-mangrove plant Myoporum bontioides (Dong etal., 2018). Both compounds showed high activity (6.5 μg/ mL) against the methicillin-resistant but vancomycin-sensitive S. aureus strain. Even more pronounced was the effect of 16, a sulfurcontaining pyridine derivative isolated from Allium stipitatum (Karunanidhi etal., 2019). The authors additionally performed a time-to-kill assay and observed bactericidal activity after 2 h. Pyridine or thiopyridine-based compounds were reported to have promising antibacterial activity before (Karunanidhi etal., 2019). In addition, compound 16 bears a carbonitrile group, which is also associated with strong antibacterial activity. Most of the discussed alkaloids exhibit only low to moderate activities against MRSA, with only a few exceptions, such as compounds 14–16. However, some compounds show auspicious potential as synergistic agents for existing antibiotics through their ability to inhibit the bacterial efflux pump. 3.2. Terpenoids 3.2.1. Monoterpenoids and sesquiterpenoids This section discusses one monoterpenoid and 17 sesquiterpenoids (Figure2), with the latter compound class being known for some FIGURE1 Chemical structures of alkaloids with reported anti-MRSA activity. Moreno Cardenas and Çiçek 10.3389/fmicb.2023.1234115 Frontiers in Microbiology 04 frontiersin.org potent antimicrobials, such as artemisinin from Artemisia annua or santonin from Artemisia cina (Li etal., 2022). The only monoterpene in this review, nodosol (17), was isolated from the marine angiosperm Cymodocea nodosa (Kontiza etal., 2008). It showed a MIC value of 16 μg/mL against strains with different resistance mechanisms. Interestingly, the compound showed higher activity than the reference antibiotics against three drug resistant strains. Four furyl bearing sesquiterpenes were isolated from Myoporum bontioides (18–21), of which two compounds display an additional dihydrofuran feature (18 and 19) (Dong etal., 2018). Interestingly, both compounds exhibited twice the activity of their ring-open counterparts (20 and 21). Compound 22 was isolated from Mentha pulegium and exhibited moderate activity with an IC 50 value of 8.5 μg/mL (Ibrahim, 2013). The dimeric sesquiterpenoid gossypol (23), which is also known from the cotton plant, was isolated from Thespesia garckeana by Masila etal. (2015) and showed an IC 50 of 4.66 μg/mL. Häkkinen etal. (2021) tested the germacranolide lactones parthenolide (24, from Tanacetum parthenium) and lactucopicrin (25, from Cichorium intybus) against a β-lactamase possessing strain, with pronounced effects (MIC value of 0.16 μg/mL). Ferula feruloides was the source for nine acetophenone sesquiterpenoids (26–34), which all exhibited activity against different MRSA strains (Sun etal., 2019). 26 (MIC: 1 to 32 μg/mL) showed the highest effect against a strain that expresses a tetK efflux pump and against an epidemic strain. Its para-methyl ether 27, in contrast, was inactive against four out of five strains, indicating the importance of the para-hydroxy group for the anti-MRSA activity. This is even more clear when looking at the additional seven acetophenone sesquiterpenes, which (apart from 30) show pronounced growth inhibition. The number of different compounds in this class allows some further conclusions. Hydroxylation in the α-position of the side chain leads to an increase in activity against almost all strains (28, MIC: 1–4 μg/mL), whereas dihydroxylation in position ω-6 and ω-7 results in significantly lower effects (30, MIC: 64 μg/mL). Conversely, the formation of a dioxolane ring in the same position (31, MIC: 0.5–16 μg/mL) causes a significant increase in activity, especially for the tetK and the epidemic strain. This increase is much less pronounced when only one of the two hydroxy groups derivatized, as, e.g., for compound 34 (MIC: 16–64 μg/mL). Formation of a cyclic lactone in the α-position leads to MIC values of 2–8 μg/mL (32) and 2–16 μg/mL (33), respectively, whereas a rearrangement of the farnesyl unit toward a non-linear side chain causes even lower activities (29). FIGURE2 Chemical structures of monoand sesquiterpenoids with reported anti-MRSA activity. Moreno Cardenas and Çiçek 10.3389/fmicb.2023.1234115 Frontiers in Microbiology 05 frontiersin.org 3.2.2. Diterpenoids This section comprises 34 diterpenoids of nine different scaffolds, of which most display meroditerpenoids (55–68) from the red algae Callophycus sp. Additionally, eight abietane type (47–54), six sphaerodiene-type 35–40, three labdane type (41, 42, and 43), two clerodane type (45 and 46), and one ent-kaurane-type (44) diterpenoid will bediscussed (Figure3). Smyrniotopoulos etal. (2008) isolated six brominated diterpenes (35–40) from the red alga Sphaerococcus coronopifolius. While compounds 35–37 and 39 were only low to moderately active, compounds 38 (MIC: 0.25 to 1 μg/mL) and 40 (MIC: 1 to 2 μg/mL) showed pronounced effects. The authors suggest that the presence of an α, β-unsaturated ketone at position C-12 may cause the activity, being able to act as a Michael-acceptor. Pfeifer Barbosa etal. (2019) isolated five diterpenoids of three different diterpenoid types (41–45) from the oleoresin of Copaifera reticulata and tested them for their anti-MRSA activity and their cytotoxicity. Kaurenoic acid (44, IC 50 of 3.4 μg/mL), kolavenic acid (45, clerodane-type) (IC 50 of 3.0 μg/mL), and 43 (labdane-type) (IC50 of 2.5 μg/mL) showed the highest activity. Interestingly, the activity was not dependent on the diterpenoid type but increased with the compounds’ lipophilicity. In a follow-up study by Çiçek etal. (2020) compounds 41 and 44 were subjected to semisynthetic derivatization targeting the exocyclic methylene group as well as the carboxylic acid functionality. Both features were found to beessential for the activity against MRSA. The second clerodane diterpene (46) was isolated by Dettweiler etal. (2020) from Callicarpa americana. It showed moderate activity (MIC: 16 μg/mL) against a β-lactam resistant strain. Zhao et al. (2021) isolated dihydrotanshinone I(47) from Salvia miltiorrhiza, which exhibited moderate effects that were proposed to result from disturbance of the cell wall and membrane. Starks etal. (2014) isolated one new and three known abietane-type diterpenoids (48–51) with pronounced activities from Taxodium ascendens, a species that was reclassified as Taxodium distichum. Out of the four compounds, 51 showed lower but broader activity with a MIC value of 4 μg/mL against five different strains. Desaturation and oxygenation in position 5 and 6, respectively, led to comparable activities (50, MIC: 1–4 μg/mL) while the exchange of a phenolic hydroxy group in position 11 toward an aliphatic alcohol (in position 3 or 29) led to a significant increase in activity against (at least) two strains (with MIC values of 1–2 μg/mL for compounds 48 and 49). Oluwatuyi etal. (2004) isolated the three abietane diterpenes, 12-methoxy-trans-carnosic acid (52), carnosic FIGURE3 Chemical structures of diterpenoids with reported anti-MRSA activity. Moreno Cardenas and Çiçek 10.3389/fmicb.2023.1234115 Frontiers in Microbiology 06 frontiersin.org acid (53), and carnosol (54), from Rosmarinus officinalis. All compounds showed low to moderate activity, with 54 being the most potent compound with a MIC value of 16 μg/mL. Thereby, the lactone bridge seems to bebeneficial for the activity compared to a free carboxylic acid. Combinations of 53 and 54 with tetracycline revealed synergistic effects against the TetK-possessing strain XU212. Compound 53, furthermore, exhibited potent synergistic effects in combination with erythromycin. Teasdale etal. (2012) isolated six brominated diterpenoids of the sphaerodiene type (55–60) from a member of the genus Callophycus. Thereby, compounds 59 and 57 were only moderately active, whereas compounds 58 and 55 showed a MIC value of 6.3 μg/mL and compounds 60 and 56 were active with a MIC value of 1.6 μg/mL. The genus Callophycus was also the source for eight halogenated meroditerpenoids (61–68). All compounds showed moderate activity, except compounds 63 (MIC: 1.4 μg/mL), 62 (MIC: 8 μg/mL), and 68 (MIC: 1.8 μg/mL), which exhibited pronounced effects (Lavoie etal., 2017). The structural complexity of this group of diterpenoids derives from the addition of a para-hydroxybenzoic acid to the diterpene scaffold either at the methyl group at position 8 (56) or at position 9 (55). Further condensation of 56 leads to the benzofuran moiety of compounds 57–60, and 61–62, respectively. Interestingly, the formation of a dihydropyran ring between the diterpene scaffold and the para-hydroxybenzoic acid moiety (as for compound 55) led to a four-fold lower activity, while the formation of a benzofuran-connected system (60) did not alter the antibacterial effect (compared to 56). Moreover, the formation of a methyl ester (61) as well as the oxygenation of the prenyl moiety (as for compounds 57–59) decreased the activity. This effect was less pronounced for the peroxide (58), though. 3.2.3. Triterpenoids In this section six cycloartane-type triterpenoids, two dammaranes, as well as one lupane, one ursane, one oleane, and one taraxastane will bediscussed (Figure4). Weaver etal. (2022) isolated 18β-glycyrrhetinic acid (69) from the roots of a Glycyrrhiza sp. The compound exhibited few effects but lowered MRSA virulence in vivo. Micromeric acid (70) was isolated by Khin etal. (2021) together with betulinic acid (72) from Rosmarinus officinalis. Thereby, 72 showed high activity (MIC: 8 μg/mL) against the community-associated strain USA 300, whereas 70 was only moderately active. Chung etal. (2011, 2014) also isolated betulinic acid (72) together with α-amyrin (71) from Callicarpa farinosa, which was later reclassified as Callicarpa tomentosa. Both compounds showed moderate activity, with subsequent mechanistic assays revealing promising results against a variety of bacterial transcription mechanisms (Chung etal., 2014). The only two triterpene glycosides (73 and 74) were isolated by Garo etal. (2009) from Oncoba manii, FIGURE4 Chemical structures of triterpenoids with reported anti-MRSA activity. Moreno Cardenas and Çiçek 10.3389/fmicb.2023.1234115 Frontiers in Microbiology 07 frontiersin.org which is now regrouped into the Camptostylus genus, both showing complete growth inhibition at 16 μg/mL. Unfortunately, not enough compound could beisolated for the determination of MIC values. Salam etal. (2021) isolated 75 from the leaves of Castanea sativa, showing only moderate anti-MRSA activity. However, further studies showed that the virulence was attenuated by 75. Five cycloartane triterpenoids were isolated by Wang etal. (2013) from Aphanamixis grandifolia, now reclassified as Aphanamixis polystachya, of which four compounds (76–79) were moderately active (with MIC values ranging from 25 to 50 μg/mL) and one compound (80) showed remarkable effects (MIC: 1.57 μg/mL). Thereby not only the hydroxy group in position 3 seems to play an important role for the activity, but also a second methyl group at position 4. 3.3. Phenolics The group of phenolics is divided into seven sections, of which some summarize several smaller compound classes (in terms of the number of compounds with anti-MRSA activity). Section 3.3.1, i.e., discusses 16 caffeic acid derivatives, of which six are chalcones, three are benzylchromanes, and two are lignans. 3.3.1. Caffeic acid derivatives The root barks of Cordia gilletii yielded ferulaldehyd (81), which exhibited moderate effects in a study by Okusa etal. (2014). Rosmarinic acid (82) and its methyl ester (83) were isolated by Sabry etal. (2022) from the stem bark of Cordia africana. While 82 was only moderately active (with a MIC value of 31.25 μg/mL), the methylated form (83) showed pronounced effects (MIC: 7.81 μg/mL). Zuo etal. (2015) isolated two biphenyl compounds, 84 and 85, from Biancaea sappan, which was previously ascribed to the genus Caesalpinia, in a bioactivity-guided isolation procedure. Both compounds showed moderate to low activity but demonstrated synergistic effects in combination with amikacin and gentamycin (Figure5). Chan etal. (2012) isolated kuraridin (86), a prenylated chalcone, from the traditional Chinese medicial plant Sophora flavescens using high-speed counter-current chromatography. The compound showed high activity (MIC: 8 μg/mL) against the efflux pump expressing strains RN4220 (macrolides) and SA-1199B (fluoroquinolones) and against a representative healthcare-associated strain (SA-ST239). Additional checkboard studies found plenty of additive effects in combination with antibiotics, suggesting that the antibacterial action is not directly related to the efflux pump inhibition. Kim etal. (2017) FIGURE5 Chemical structures of caffeic acid derivatives with reported anti-MRSA activity. Moreno Cardenas and Çiçek 10.3389/fmicb.2023.1234115 Frontiers in Microbiology 08 frontiersin.org isolated licochalcone A (87) and E (88) from Glycyrrhiza inflata, also known as Chinese licorice. Both compounds showed moderate to high activity (MIC: 10 to 20 μg/mL) against six different strains, even partly surpassing the effect of the positive controls. Lee etal. (2009) tested the dihydrochalcone phloretin (89), which was obtained from a compound library. With low toxicity and a MIC value of 16 μg/mL, the authors suggest that the activity against MRSA correlates with the high affinity to the β-ketoacyl-acyl carrier potein synthase III (KASIII), a functional enzyme in the bacterial fatty acid biosynthesis. Bocquet etal. (2019) extracted eight different prenylated phenolic compounds from the female inflorescences of Humulus lupulus, which are used for beer brewing. Xanthohumol (90) was significantly active with a MIC value of 9.8 μg/mL, while desmethylxanthohumol (91) showed only moderate activity against the tested clinical isolates. Moreover, xanthohumol (90) displayed synergistic effects in combination with gentamycin, ciprofloxacin, oxacillin, and rifampicin. Honokiol (92) and magnolol (93), two lignans from the stem bark of a non-specified member of the genus Magnolia, which is used in traditional Chinese and Japanese medicine, were studied by Chiu etal. (2021). Both compounds demonstrated high activity against MRSA (MIC: 10 μg/mL). Further investigations showed that both compounds repressed the expression of mecA, a gene that is important for the β-lactam resistance of S. aureus. Additionally, both compounds decreased the biofilm formation in a sub-MIC concentration, which may result from repressing biofilm formation related genes. Zuo etal. (2014) isolated three 3-benzylchroman derivatives (94–96) from the heartwood of the Chinese drug Caesalpinia sappan (now Biancaea sappan). The compounds showed low to moderate activity with MIC values ranging from 16 to 64 μg/ mL. Further studies revealed high synergistic effects of brazilin (94) with gentamycin, etimicin, and streptomycin and of brazilein (95) with azithromycin, gentamycin, and ceftazidime, repectively. 3.3.2. Flavonoids The present section discusses eight flavonols, four flavones, three flavanones, two flavans, and one flavanone (Figure6). Prenylated flavonoids will bedealt with in the subsequent section (3.3.3). Koagne etal. (2018) isolated 97 and 98 together with two alkaloids from Crinum distichum, which was reclassified as Crinum ornatum. FIGURE6 Chemical structures of flavonoids with reported anti-MRSA activity. Moreno Cardenas and Çiçek 10.3389/fmicb.2023.1234115 Frontiers in Microbiology 09 frontiersin.org Both compounds showed moderate activity against a not further specified MRSA strain (Koagne etal., 2018). Alhadrami etal. (2020) performed a structure-based inverse virtual screening, discovering the penicillin-binding protein 2a (PBP2a) as a potential target for their flavonoid database. PBP2a mediates the antibacterial and antibiotic-synergistic effect of the tested compounds. Subsequently, 23 different flavonoids were investigated, of which quercetin (102, MIC: 62.5 μg/mL), apigenin (100, MIC: 31.25 μg/mL), chrysin (101, MIC: 15.62 μg/mL), and hesperetin (99, MIC: 31.25 μg/mL) showed the highest activity against the methicillin-resistant strain ATCC 33591. Because the activity negatively correlated with the number of free hydroxy groups the authors concluded that a lower polarity is beneficial for the positive effects. Pang etal. (2022) isolated morin (103) from Morus alba with a low activity (100 μg/mL). Lee et al. (2009) performed a receptor-oriented pharmacophore-based in silico screening for new inhibitors of the bacterial fatty acid synthase (FAS), revealing 3,6-dihydroxyflavone (104) as a potent compound against MRSA (with a MIC value of 16 μg/mL). Commiphora pedunculata, a traditionally used medicinal plant species common in Africa, Arabia, and the Indian subcontinent, is the source of dihydrokaempferol (105), which displayed moderate activity against a clinical isolate (Tajuddeen etal., 2014). Oluwatuyi etal. (2004) investigated 106 from Rosmarinus officinalis against three different drug-resistant strains. Thereby, the highest activity (16 μg/ mL) was found against the tetracycline efflux pump possessing strain. Nzogong et al. (2018) isolated 107 and 110, two lowto moderately active glycosylated flavonoids from Dissotis senegambiensis, which was regrouped into the genus Antherotoma, along with four triterpenoids and five tannins. Two flavanonol rhamnosides (108 and 109) were isolated by An etal. (2011) from Hypericum japonicum and tested against 10 methicillin-resistant and one methicillin-sensitive strain. While 108 was affecting all tested strains, 109 was only inhibiting three strains. However, MIC values of both compounds were only at a moderate to low level (ranging from 32 to 64 μg/mL). The glycosylated flavonoids with the highest activity were isolated from the leaves of Platanus occidentalis, the American sycamore (111–114) (Ibrahim et al., 2009). All four compounds display kaempferol 3-O-dicoumaroylrhamnosides, with different geometric isomerism for the coumaroyl moieties. Thereby, the derivative bearing two trans-coumaroyl moieties (111) exhibited the lowest activity (MIC value of 10 μg/mL), while two cis-coumaroyl moieties (114) led to a MIC value of 0.6 μg/mL and thus to a very FIGURE7 Chemical structures of prenylated flavonoids with reported anti-MRSA activity. Moreno Cardenas and Çiçek 10.3389/fmicb.2023.1234115 Frontiers in Microbiology 16 frontiersin.org TABLE1 Overview on additive and synergistic effects with existing antibiotics indicated by FICI values and combined MIC values, respectively. No. MRSA strain Amikacin Ampicillin Azithromycin Ceftazidime Ciprofloxacin Gentamicin Levofloxacin Norfloxacin Oxacillin Additional antibiotics References 4 MRSA-011 0.5 Zeng etal. (2022) MRSA-003 0.375 5 MRSA-011 0.5 Zeng etal. (2022) MRSA-003 0.5 7 ATCC 33591 Ethidium bromide: 7.8 μg/mL (2×) Zuo etal. (2011) 9 OMS 7 0.625 0.5 Yu etal. (2005) MRSA 004 0.375 0.5 Zuo etal. (2012) MRSA 055 0.25 0.375 MRSA 123 0.25 0.375 MRSA 144 0.375 0.5 MRSA 189 0.375 0.5 MRSA 240 0.625 0.75 MRSA 276 0.375 0.5 MRSA 294 0.5 0.375 MRSA 328 0.25 0.375 MRSA 330 0.188 0.5 10 MRSA 004 0.281 0.375 Zuo etal. (2012) MRSA 055 0.156 0.25 MRSA 123 0.375 0.188 MRSA 144 0.375 0.5 MRSA 189 0.5 0.188 MRSA 240 0.5 0.5 MRSA 276 0.375 0.5 MRSA 294 0.281 0.5 MRSA 328 0.5 0.375 MRSA 330 0.313 0.5 11 SA1199B 0.375 Yu etal. (2019) 46 ATCC 43300 0.25 μg/mL (256×)/0.125 Meropenem: 0.094 Dettweiler etal. (2020) Vancomycin: 0.625 (Continued) Moreno Cardenas and Çiçek 10.3389/fmicb.2023.1234115 Frontiers in Microbiology 17 frontiersin.org No. MRSA strain Amikacin Ampicillin Azithromycin Ceftazidime Ciprofloxacin Gentamicin Levofloxacin Norfloxacin Oxacillin Additional antibiotics References 53 XU212 Tetracycline: 64 μg/ mL (2×) Oluwatuyi etal. (2004) RN4220 Erythromycin: 32 μg/mL (8×) SA1199B 32 μg/mL (1×) Ethidium bromide: 8 μg/mL (2×) 54 XU212 Tetracycline: 32 μg/ mL (4×) Oluwatuyi etal. (2004) RN4220 Erythromycin: 256 μg/mL (1×) SA1199B 32 μg/mL (1×) 84 MRSA 0.313–1 0.5–1 0.75–1.5 Cefazolin: 0.625–2 Zuo etal. (2015) 85 MRSA 0.078–1 0.313–1 Amoxicillin: 0.625–2 Zuo etal. (2015) 90 T28.1 0.49–1 0.14–1 0.28–0.75 Rifampicin: 0.25–0.75 Bocquet etal. (2019) 91 T28.1 0.38–1.5 0.03–0.28 0.5–0.76 Rifampicin: 1–5 Bocquet etal. (2019) 94 MRSA 0.25–2 0.25–1 Etimicin: 0.375–0.75 Zuo etal. (2014) Strepomycin: 0.25–1 95 MRSA 0.47–0.75 0.188–2 0.375–1 Penicillin: 0.625–1 Zuo etal. (2014) 96 MRSA 0.625–1 0.5–1 0.75–1.5 Cefazolin: 0.75–2 Zuo etal. (2014) 108 MRA 004 0.5 1.5 0.25 0.312 An etal. (2011) MRA 055 0.625 1 0.25 0.312 MRA 092 0.5 1 0.187 0.5 MRA 123 0.5 1 0.25 0.25 MRA 144 2 1 0.375 0.5 MRA 155 1 1.5 0.25 0.375 MRA 189 1 1.5 0.187 0.5 MRA 247 0.75 1.5 0.375 0.375 MRA 328 2 1 0.25 0.375 MRA 330 0.625 1.5 0.375 0.312 116 ATCC 43300 0.16 0.13 0.14 Tetracycline: 0.14 Aelenei etal. (2020) (Continued) TABLE1 (Continued) Moreno Cardenas and Çiçek 10.3389/fmicb.2023.1234115 Frontiers in Microbiology 18 frontiersin.org TABLE1 (Continued) No. MRSA strain Amikacin Ampicillin Azithromycin Ceftazidime Ciprofloxacin Gentamicin Levofloxacin Norfloxacin Oxacillin Additional antibiotics References 122 MRSA 1903 0.625 Navrátilová etal. (2016) MRSA 3202 0.375 MRSA 62097 1.008 MRSA 67755 0.508 MRSA 1679 0.266 123 MRSA 1903 0.266 Navrátilová etal. (2016) MRSA 63718 1.031 MRSA 3202 0.5 MRSA 62097 0.563 MRSA 67755 1.008 MRSA 1679 0.625 127 ATCC 43300 0.38 0.19 0.27 Tetracycline: 0.38 Aelenei etal. (2020) 128 ATCC 29213 0.135 Meenu etal. (2021) 140 ATCC 1708 Meropenem: 0.375 Kumarihamy etal. (2022) Vancomycin: 1 187 ATCC 33591 0.5 0.5 Lee etal. (2010) DPS-1 0.5 0.5 DPS-2 0.5 0.5 DPS-3 0.5 0.5 DPS-4 0.37 0.5 DPS-5 0.5 0.5 DPS-6 0.5 0.75 DPS-7 0.5 0.5 DPS-8 0.5 0.5 DPS-9 0.37 0.5 DPS-10 0.5 0.5 DPS-11 0.37 0.5 DPS-12 0.37 0.5 DPS-13 0.37 0.5 DPS-14 0.5 0.37 DPS-15 0.37 0.5 190 T28.1 0.63–1 9 0.19–1.25 Rifampicin: 2.2–6 Bocquet etal. (2019) Moreno Cardenas and Çiçek 10.3389/fmicb.2023.1234115 Frontiers in Microbiology 19 frontiersin.org potentiating the effect of a compound but are also needed to increase the compounds’ bioavailability and physical properties. For example, phenolic compounds, such as flavonoids, are rapidly eliminated, whereas many terpenoids show low solubility in aqueous solutions. Here, biotechnological approaches could guarantee provision of highpurity compounds that are produced in bioreactors. However, this requires understanding of the biosynthetic pathways leading to the natural product of interest, which currently is not the case for many plant species (Porras etal., 2021). Here, computational techniques such as genome mining and the use of genomic and transcriptomic databases show possible approaches to enable the synthesis of natural products in microorganisms. Alternatively, plant species such as Nicotiana benthamiana could serve as producing organisms, being more closely related and thus more suitable to create, e.g., glycosylated natural products (Molina-Hidalgo etal., 2021). 5. Summary and conclusion In this review a total of 223 plant natural products from more than 20 different compound classes are presented and discussed. Though most of the reported compounds display moderate effects, with activities ranging from 10 to 50 μg/mL, a few exceptions act at low or even submicromolar concentrations. Two such compounds are the sesquiterpene lactones parthenolide (24) and lactupicrin (25), both showing a MIC value of 0.16 μg/mL. In addition, the subclass of acetophenone sesquiterpenes present a set of interesting candidates, with four compounds displaying pronounced effects (26–28, 31). Similarly, the subclass of meroditerpenes, which also originate from two different biosynthetic pathways, yield several highly active constituents (56, 60, 63, 68), with MIC values between 1.4 and 1.8 μg/ mL. Further potent diterpenes were found in the class of abietanes (48, 49) and sphaerodienes (38, 40), respectively. Of note, for compound 38 MIC values of 0.25–1 μg/mL against five different strains have been determined. The class of triterpenoids only revealed one interesting compound (80), as did the class of alkaloids (6). However, many of the reported alkaloids displayed synergistic effects with existing antibiotics, which result from the inhibition of the bacterial efflux pump. (Table1) Strong synergistic effects (with ciprofloxacin, gentamicin, oxacillin, and tetracycline) were also reported for the prenylated flavones morusin (116) and kuwanon G (127). Likewise, taxifolin 7-O-α-L-rhamnopyranoside (108), displayed synergism with ceftazidime and levofloxacin, but was only slightly active alone. Three flavonol dicoumaroylrhamnosides (112–114), in contrast, exhibited pronounced effects with MIC values of 1.7–0.6 μg/mL. Other interesting phenolic compounds were found in the classes of isoflavonoids (132), xanthones (170, 171), anthranoids (187, 191), and above all, in the class of phloroglucinols. Here, several compounds exhibited remarkable effects, such as lupulone (194, MIC values of 0.6–1.2 μg/mL), ivesinol (203, MIC: 0.31 μg/mL), rhodomyrtone (204, MIC: 0.5 μg/mL), aspidinol (205, MIC: 0.5–2 μg/mL), and hyperforin (206, MIC: 0.5–2 μg/mL), thus rendering phloroglucinol derivatives the most promising compound class for further drug development. Finally, two rather unusual plant natural products have been reported, which were the cyclopentapyran 213 (with a MIC value of 1 μg/mL) and the macrolide neurymenolide A (214, with an IC 50 value of 0.77 μg/mL). In summary, several compounds with pronounced and/or synergistic effects against Methicillin-resistant Staphylococcus aureus have been isolated from plant species. Some of them even showed MIC values comparable to the established antibiotics vancomycin, daptomycin, tigecycline, and linezolid, respectively (Niveditha and Sujatha, 2015). Still, none of the mentioned compounds managed to proceed toward a commercial antibiotic drug. Whether the restricted activity to only a few out of several strains or their limited availability were the reason to not further develop the respective compounds could not bedetermined. In the latter case, the future will show if emerging biotechnological methods will help to provide higher amounts of natural products for subsequent clinical studies or semi-synthetic and technological modifications. In addition, more comprehensive approaches, e.g., studies with enriched extracts or defined fractions, may present an alternative for some stages in drug development. And last but not least, ethnopharmacological research will have to adapt to international conventions, e.g., the Nagoya protocol, taking them as what they are, namely measures to protect biodiversity and natural heritage and not obstacles in drug discovery. Author contributions CMC conducted the literature search, organized the data, and wrote the original draft. SÇ was reviewing, writing, and editing the original draft, supervising the work, and acquiring the funding for publication. All authors contributed to the article and approved the submitted version. Funding The authors acknowledged financial support by the DFG within the funding program “Open Access-Publikationskosten”. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could beconstrued as a potential conflict of interest. Publisher’s note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. 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