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

F on ie s in Mic obiology 01 on ie sin.o g S uc u e-dependen ac i i y o plan na u al p oduc s agains me hicillin- esis an S aphylococcus au eus Calis oMo eno Ca denas and Se ha S.Çiçek * Depa men o Pha maceu ical Biology, Ins i u e o Pha macy, Kiel Uni e si y, Kiel, Ge many Me hicillin- esis an S aphylococcus au eus (MRSA) is one o he majo causes o nosocomial in ec ions and has been classi ied as “high p io i y pa hogen” by he Wo ld Heal h O ganiza ion. I s abili y o de elop esis ances has been a challenge o he las decades and is s ill a h ea o heal h ca e sys ems, as s ains wi h esis ances o he so-called d ugs o las eso ha e been disco e ed. The e o e, new an ibio ics a e u gen ly needed. Na u al p oduc s a e an impo an sou ce o he de elopmen o new d ugs, he eby mos ly se ing as lead compounds o u he modi ica ion. In his e iew, he da a on plan na u al p oduc s wi h epo ed an i-MRSA ac i i y un il he end o 2022 is discussed, highligh ing he mos e ec i e d ugs wi h espec o hei inhibi o y concen a ions as well as wi h ega d o e en ual syne gis ic e ec s wi h exis ing an ibio ics. In he la e sense, he class o alkaloids mus bemen ioned, exhibi ing addi i e o syne gis ic e ec s by inhibi ing bac e ial e lux pumps. Wi h ega d o he an ibio ic ac i i y, phlo oglucinol de i a i es ce ainly belong o he mos p omising compounds, e ealing se e al candida es wi h ema kable e ec s, e.g., lupulone, i esinol, hodomy one, aspidinol, o hype o in. Also, he class o e penoids yielded no ewo hy compounds, such as he sesqui e pene lac ones pa henolide and lac opic in as well as ace ophenone sesqui e penes and sphae odiene ype di e penoids, espec i ely. In addi ion, p onounced e ec s we e obse ed o he mac olide neu ymenolide A and h ee la onol dicouma oyl hamnosides. KEYWORDS MRSA, na u al p oduc , an imic obial esis ance, an ibio ic, phlo oglucinol, sesqui e penoid, di e penoid, mac olide 1. In oduc ion Due o he inc easing age o he popula ion, especially in indus ialized na ions, hospi al o nu sing home-acqui ed in ec ions a e becoming a majo p oblem (Hasanpou e al., 2023). An imic obial esis ance is p ognosed o cause 10 million annual dea hs by he yea 2050, ende ing i he second leading cause o dea h a e ca dio ascula diseases (Nandhini e al., 2022). Many o hese in ec ions a e associa ed wi h me hicillin- esis an S aphylococcus au eus (MRSA), which has a mo ali y a e o a ound 14% in pa ien s wi h d ug- esis an in ec ions in he US (CDC, 2013). Howe e , he p e alence o heal hca e-associa ed MRSA a ies o di e en coun ies, wi h, e.g., Po ugal (58.4%), Pakis an (52%), India (46%), China (45%), and No way (38.9%) showing high a ios, while o he coun ies such as Mexico (19.1%), Aus alia (15.1%), and Ge many (4.6%) a e much less a ec ed (Shoaib e  al., 2022). E en hough he i s obse a ion o esis ance da es back o he 1960s (Je ons, 1961), MRSA is s ill a h ea o OPEN ACCESS EDITED BY Guang ao Zhang, Binzhou Medical Uni e si y, China REVIEWED BY Cla issa Si , Sain Ma y's Uni e si y, Canada Ri esh Raju, Wes e n Sydney Uni e si y, Aus alia Chunshuai Huang, Shanghai Ins i u e o Ma e ia Medica (CAS), China *CORRESPONDENCE Se ha S. Çiçek [email p o ec ed] RECEIVED 03 June 2023 ACCEPTED 14 July 2023 PUBLISHED 15 Augus 2023 CITATION Mo eno Ca denas C and Çiçek SS (2023) S uc u e-dependen ac i i y o plan na u al p oduc s agains me hicillin- esis an S aphylococcus au eus. F on . Mic obiol. 14:1234115. doi: 10.3389/ micb.2023.1234115 COPYRIGHT © 2023 Mo eno Ca denas and Çiçek. This is an open-access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License (CC BY). The use, dis ibu ion o ep oduc ion in o he o ums is pe mi ed, p o ided he o iginal au ho (s) and he copy igh owne (s) a e c edi ed and ha he o iginal publica ion in his jou nal is ci ed, in acco dance wi h accep ed academic p ac ice. No use, dis ibu ion o ep oduc ion is pe mi ed which does no comply wi h hese e ms. TYPE Re iew PUBLISHED 15 Augus 2023 DOI 10.3389/ micb.2023.1234115 Mo eno Ca denas and Çiçek 10.3389/ micb.2023.1234115 F on ie s in Mic obiology 02 on ie sin.o g heal h-ca e sys ems, e ol ing mo e and mo e esis ance mechanisms agains a b oad spec um o an ibio ics. Apa om communi y- associa ed MRSA s ains, li es ock-associa ed s ains also se e as a ese oi o esis ance (Cuny e  al., 2013). In 2017, MRSA was classi ied as a “high p io i y pa hogen” by he wo ld heal h o ganiza ion (WHO, 2017), s a ing he u gen need o de elop new ea men s agains his bac e ium, i.e., new subs ances wi h an ibio ic o an ibio ilm ac i i y. MRSA causes di e en kinds o in ec ions including bac e emia, skin and so - issue in ec ions, in ec i e endoca di is, os eoa icula in ec ions, pleu opulmona y in ec ions, and many mo e (Tong e al., 2015). This o en leads o complica ions o p olonga ion o clinical ea men s. In he Eu opean Union, MRSA causes he second mos in ec ions o any d ug- esis an pa hogen, only su passed by he cephalospo in- esis an Esche ichia coli (ECDC, 2021). The ea men includes an ibio ics o he so-called d ugs o las eso (DoLR) like ancomycin, dap omycin, linezolid, and igecycline (Choo and Chambe s, 2016; Sub amani e al., 2017). Ala mingly, s ains wi h esis ance o one o hese an ibio ics ha e al eady been de ec ed (Laye e al., 2021). An o e iding cause o he de elopmen o mic obial esis ance is he misuse o an ibio ics (Ab eu e al., 2012; Peacock and Pa e son, 2015; Rossi e e al., 2017). Mos esis ance mechanisms a ec he up ake and e lux o he an ibio ic, al e he a ge s uc u e, modi y he an ibio ic, o e en p oduce enzymes o inac i a e he an ibio ic (Peacock and Pa e son, 2015; Rossi e e al., 2017). I a s ain adop s a esis ance he espec i e gene can bepassed along h ough di ision o ho izon al gene ans e (Peacock and Pa e son, 2015; Ál a ez- Ma ínez e al., 2020). Because mos o he a ailable an ibio ics agains MRSA a ge he cell wall biosyn hesis, new lead compounds wi h o he bac e ios a ic o bac e icidal mechanisms a e u gen ly needed (Choo and Chambe s, 2016). In he pas , se e al na u al p oduc s ha e led o e ec i e an ibio ics, such as penicillin and ancomycin, wi h, howe e , a g ea e ocus on ungal o bac e ia-de i ed compounds (Ka z and Bal z, 2016; W igh , 2017; Po as e al., 2021). Ne e heless, plan s a e a ich sou ce o di e se lead compounds, such as alkaloids, e penoids, quinones, o polyphenols. These subs ances p o ec o ganisms agains ha m ul bac e ia, ungi, and insec s, he eby o e ing g ea e s uc u al a ie y han s anda d small molecule lib a ies (Sub amani e al., 2017; Zaynab e al., 2018; A anaso e al., 2021). Conside ing he ac ha no new an ibio ic class has been app o ed by he FDA since he la e 1980s, he b oad di e si y o specialized plan me aboli es may con ibu e o he de elopmen o u u e an imic obials (Du and e al., 2019). The adi ional use o medicinal plan species agains nume ous kinds o in ec ious diseases is a good s a ing poin o he explo a ion o new an ibio ic lead s uc u es (Anand e  al., 2019; Po as e  al., 2021). Some plan ex ac s a e al eady used o he ea men o skin in ec ions caused by MRSA, such as he essen ial oil om he ea ee Melaleuca al e ni olia (My aceae) (Nandhini e al., 2022). In addi ion, no only he pu e an ibio ic e ec is o in e es , bu also po en ial addi i e o syne gis ic e ec s wi h exis ing an ibio ics migh bean app oach agains adap ed esis ances (Sadee and Mahomoodally, 2021). In he ollowing, 223 na u al p oduc s om a ious plan species a e discussed wi h ega d o hei s uc u e and an ibac e ial e ec s agains 169 di e en MRSA s ains (Supplemen a y Table S1) as well as o hei syne gis ic e ec s wi h a ange o di e en an ibio ics. 2. Me hods A li e a u e sea ch was ca ied ou using he Web o Science ci a ion index, including all publica ions published un il he end o 2022. The sea ch e ms “MRSA” and “na u al p oduc s” we e used yielding 833 esul s. These we e educed o he ield o plan science esul ing in 148 hi s. Also, o he sou ces we e collec ed, which we e no ound by da abase sea ch wi h he p e ious e ms, yielding a o al o 223 plan na u al p oduc s wi h epo ed an i-MRSA ac i i y. The compounds we e so ed by compound class, he eby aking compound names and con igu a ions “as is” om he o iginal publica ions. Plan s species names we e checked using he “Wo ld Flo a Online” and e en ually changed in o he accep ed axa. MIC/IC50 alues a e gi en in μg/mL using he numbe o digi s gi en in he o iginal publica ions. Values ound μmol/mL we e con e ed o μg/mL. Values abo e 100 μg/mL we e conside ed inac i e and hus excluded om he e iew. Ac i i ies abo e 50 μg/mL we e e e ed o as low, MIC and IC50 alues om 10 o 50 μg/mL as mode a e and alues below 10 μg/ mL as high. Fo syne gis ic e ec s ac o ial inhibi o y concen a ion index (FICI) alues abo e 2 indica e an agonism, alues o 2 o 1 indi e ence, alues o 0.5 o 1 addi i e e ec s, and alues below 0.5 syne gism. The alues gi en in μg/mL ep esen he MIC o he combina ion. 3. Resul s and discussion 3.1. Alkaloids The i s compound class o bediscussed in his e iew is he class o alkaloids, which a e a ich sou ce o analge ic o cy os a ic d ugs, bu a e a he a e in he ield o an ibio ics. Howe e , hey ac ed as lead subs ances in he de elopmen o quinolones, hus emaining impo an sca olds in d ug de elopmen (Cushnie e al., 2014). Ou li e a u e sea ch e ealed mos epo s o isoquinolines- ype alkaloids wi h a o al o eigh compounds. Addi ionally, wo lyco ine de i a i es, wo py olin-2-on de i a i es, wo phenan h idine- ype alkaloids, one quinolone, and one py idine-de i a i e we e epo ed (Figu e1). Cou oupi a guianensis, which is used in adi ional Sou h Ame ican medicine, yielded 1, a compound wi h a low MIC alue bu also low oxici y (Cos a e al., 2017). Liu e al. (2021) ex ac ed wo isoquinolines (2 and 3) om Do ypho a a oma ica lea es, wi h ac i i ies anging om 9.9 o 39.6 μg/mL (2) and om 19.7 o 39.4 μg/ mL (3), espec i ely. Bo h compounds we e i s es ed agains me hicillin-sensi i e S aphylococcus au eus and showed highe ac i i y agains he esis an clinical isola es. Ano he wo isoquinolines (4 and 5) we e isola ed om he oo s o Zan hoxylum ni idum by Zeng e al. (2022). Compound 4 showed mode a e and compound 5 showed low ac i i y agains MRSA, bu bo h exhibi ed p onounced syne gis ic e ec s wi h ampicillin, which we e a ibu ed o he inhibi ion o he bac e ial e lux pump. Compound 4 was, u he mo e, ound o success ully dis u b he bac e ial bio ilm. Compound 6, a quinolone de i a i e was isola ed om Zan hoxylum sch ebe i, o me ly named Zan hoxylum monophylum, and displayed an IC 50 alue o 1.5 μg/mL, which was a he low compa ed o he posi i e con ol cip o loxacin (IC 50 o 0.06 μg/mL) (Rod íguez- Guzmán e  al., 2010). Zuo e  al. (2011) isola ed wo Mo eno Ca denas and Çiçek 10.3389/ micb.2023.1234115 F on ie s in Mic obiology 03 on ie sin.o g bisbenzylisoquinoline alkaloids (7 and 8) om S ephania e and a, a adi ional d ug in Chinese medicine, wi h bo h compounds showing low ac i i y. Yu e al. (2005) and Zuo e al. (2012) bo h s udied compound 9, an isoquinoline alkaloid om Cop is chinensis agains di e en clinical isola es esul ing in low o mode a e an ibac e ial e ec s. Howe e , he compound was ound o p e en he bac e ium om adhesion and in asion in o human gingi al ib oblas s, hus also a ec ing he i ulence o MRSA. Addi ionally, Zuo e al. (2012) isola ed 10, om Cop is chinensis, showing a sligh ly highe ac i i y han 9. Mo eo e , 9 and 10 showed syne gis ic e ec s wi h di e en an ibio ics. Also he e, he syne gis ic e ec was a ibu ed o he inhibi ion o he bac e ial e lux pump. Yu e al. (2019) es ed 11 agains an MRSA s ain ha o e exp essed he No A mul id ug e lux pump, hus gi ing in e ences o many wild ype- MRSA s ains. While 11 was only sligh ly ac i e when es ed alone, a combina ion wi h no loxacin o ese pine led o an eigh old inc ease in he an ibio ic ac i i y. The e o e, 11 was assumed an e lux pump inhibi o and sugges ed o be u he in es iga ed. The wo lyco ine de i a i es 12 and 13 we e isola ed om C inum o na um, o me ly e e ed o as C inum dis ichum, by Koagne e al. (2018) and showed mode a e ac i i y. Two sesqui e pene alkaloids (14 and 15) we e isola ed om he semi-mang o e plan Myopo um bon ioides (Dong e al., 2018). Bo h compounds showed high ac i i y (6.5 μg/ mL) agains he me hicillin- esis an bu ancomycin-sensi i e S. au eus s ain. E en mo e p onounced was he e ec o 16, a sul u - con aining py idine de i a i e isola ed om Allium s ipi a um (Ka unanidhi e al., 2019). The au ho s addi ionally pe o med a ime- o-kill assay and obse ed bac e icidal ac i i y a e 2 h. Py idine o hiopy idine-based compounds we e epo ed o ha e p omising an ibac e ial ac i i y be o e (Ka unanidhi e al., 2019). In addi ion, compound 16 bea s a ca boni ile g oup, which is also associa ed wi h s ong an ibac e ial ac i i y. Mos o he discussed alkaloids exhibi only low o mode a e ac i i ies agains MRSA, wi h only a ew excep ions, such as compounds 14–16. Howe e , some compounds show auspicious po en ial as syne gis ic agen s o exis ing an ibio ics h ough hei abili y o inhibi he bac e ial e lux pump. 3.2. Te penoids 3.2.1. Mono e penoids and sesqui e penoids This sec ion discusses one mono e penoid and 17 sesqui e penoids (Figu e2), wi h he la e compound class being known o some FIGURE1 Chemical s uc u es o alkaloids wi h epo ed an i-MRSA ac i i y. Mo eno Ca denas and Çiçek 10.3389/ micb.2023.1234115 F on ie s in Mic obiology 04 on ie sin.o g po en an imic obials, such as a emisinin om A emisia annua o san onin om A emisia cina (Li e al., 2022). The only mono e pene in his e iew, nodosol (17), was isola ed om he ma ine angiospe m Cymodocea nodosa (Kon iza e al., 2008). I showed a MIC alue o 16 μg/mL agains s ains wi h di e en esis ance mechanisms. In e es ingly, he compound showed highe ac i i y han he e e ence an ibio ics agains h ee d ug esis an s ains. Fou u yl bea ing sesqui e penes we e isola ed om Myopo um bon ioides (18–21), o which wo compounds display an addi ional dihyd o u an ea u e (18 and 19) (Dong e al., 2018). In e es ingly, bo h compounds exhibi ed wice he ac i i y o hei ing-open coun e pa s (20 and 21). Compound 22 was isola ed om Men ha pulegium and exhibi ed mode a e ac i i y wi h an IC 50 alue o 8.5 μg/mL (Ib ahim, 2013). The dime ic sesqui e penoid gossypol (23), which is also known om he co on plan , was isola ed om Thespesia ga ckeana by Masila e al. (2015) and showed an IC 50 o 4.66 μg/mL. Häkkinen e al. (2021) es ed he ge mac anolide lac ones pa henolide (24, om Tanace um pa henium) and lac ucopic in (25, om Cicho ium in ybus) agains a β-lac amase possessing s ain, wi h p onounced e ec s (MIC alue o 0.16 μg/mL). Fe ula e uloides was he sou ce o nine ace ophenone sesqui e penoids (26–34), which all exhibi ed ac i i y agains di e en MRSA s ains (Sun e al., 2019). 26 (MIC: 1 o 32 μg/mL) showed he highes e ec agains a s ain ha exp esses a e K e lux pump and agains an epidemic s ain. I s pa a-me hyl e he 27, in con as , was inac i e agains ou ou o i e s ains, indica ing he impo ance o he pa a-hyd oxy g oup o he an i-MRSA ac i i y. This is e en mo e clea when looking a he addi ional se en ace ophenone sesqui e penes, which (apa om 30) show p onounced g ow h inhibi ion. The numbe o di e en compounds in his class allows some u he conclusions. Hyd oxyla ion in he α-posi ion o he side chain leads o an inc ease in ac i i y agains almos all s ains (28, MIC: 1–4 μg/mL), whe eas dihyd oxyla ion in posi ion ω-6 and ω-7 esul s in signi ican ly lowe e ec s (30, MIC: 64 μg/mL). Con e sely, he o ma ion o a dioxolane ing in he same posi ion (31, MIC: 0.5–16 μg/mL) causes a signi ican inc ease in ac i i y, especially o he e K and he epidemic s ain. This inc ease is much less p onounced when only one o he wo hyd oxy g oups de i a ized, as, e.g., o compound 34 (MIC: 16–64 μg/mL). Fo ma ion o a cyclic lac one in he α-posi ion leads o MIC alues o 2–8 μg/mL (32) and 2–16 μg/mL (33), espec i ely, whe eas a ea angemen o he a nesyl uni owa d a non-linea side chain causes e en lowe ac i i ies (29). FIGURE2 Chemical s uc u es o mono- and sesqui e penoids wi h epo ed an i-MRSA ac i i y. Mo eno Ca denas and Çiçek 10.3389/ micb.2023.1234115 F on ie s in Mic obiology 05 on ie sin.o g 3.2.2. Di e penoids This sec ion comp ises 34 di e penoids o nine di e en sca olds, o which mos display me odi e penoids (55–68) om he ed algae Callophycus sp. Addi ionally, eigh abie ane ype (47–54), six sphae odiene- ype 35–40, h ee labdane ype (41, 42, and 43), wo cle odane ype (45 and 46), and one en -kau ane- ype (44) di e penoid will bediscussed (Figu e3). Smy nio opoulos e al. (2008) isola ed six b omina ed di e penes (35–40) om he ed alga Sphae ococcus co onopi olius. While compounds 35–37 and 39 we e only low o mode a ely ac i e, compounds 38 (MIC: 0.25 o 1 μg/mL) and 40 (MIC: 1 o 2 μg/mL) showed p onounced e ec s. The au ho s sugges ha he p esence o an α, β-unsa u a ed ke one a posi ion C-12 may cause he ac i i y, being able o ac as a Michael-accep o . P ei e Ba bosa e al. (2019) isola ed i e di e penoids o h ee di e en di e penoid ypes (41–45) om he oleo esin o Copai e a e icula a and es ed hem o hei an i-MRSA ac i i y and hei cy o oxici y. Kau enoic acid (44, IC 50 o 3.4 μg/mL), kola enic acid (45, cle odane- ype) (IC 50 o 3.0 μg/mL), and 43 (labdane- ype) (IC50 o 2.5 μg/mL) showed he highes ac i i y. In e es ingly, he ac i i y was no dependen on he di e penoid ype bu inc eased wi h he compounds’ lipophilici y. In a ollow-up s udy by Çiçek e al. (2020) compounds 41 and 44 we e subjec ed o semi- syn he ic de i a iza ion a ge ing he exocyclic me hylene g oup as well as he ca boxylic acid unc ionali y. Bo h ea u es we e ound o beessen ial o he ac i i y agains MRSA. The second cle odane di e pene (46) was isola ed by De weile e al. (2020) om Callica pa ame icana. I showed mode a e ac i i y (MIC: 16 μg/mL) agains a β-lac am esis an s ain. Zhao e  al. (2021) isola ed dihyd o anshinone I(47) om Sal ia mil io hiza, which exhibi ed mode a e e ec s ha we e p oposed o esul om dis u bance o he cell wall and memb ane. S a ks e al. (2014) isola ed one new and h ee known abie ane- ype di e penoids (48–51) wi h p onounced ac i i ies om Taxodium ascendens, a species ha was eclassi ied as Taxodium dis ichum. Ou o he ou compounds, 51 showed lowe bu b oade ac i i y wi h a MIC alue o 4 μg/mL agains i e di e en s ains. Desa u a ion and oxygena ion in posi ion 5 and 6, espec i ely, led o compa able ac i i ies (50, MIC: 1–4 μg/mL) while he exchange o a phenolic hyd oxy g oup in posi ion 11 owa d an alipha ic alcohol (in posi ion 3 o 29) led o a signi ican inc ease in ac i i y agains (a leas ) wo s ains (wi h MIC alues o 1–2 μg/mL o compounds 48 and 49). Oluwa uyi e al. (2004) isola ed he h ee abie ane di e penes, 12-me hoxy- ans-ca nosic acid (52), ca nosic FIGURE3 Chemical s uc u es o di e penoids wi h epo ed an i-MRSA ac i i y. Mo eno Ca denas and Çiçek 10.3389/ micb.2023.1234115 F on ie s in Mic obiology 06 on ie sin.o g acid (53), and ca nosol (54), om Rosma inus o icinalis. All compounds showed low o mode a e ac i i y, wi h 54 being he mos po en compound wi h a MIC alue o 16 μg/mL. The eby, he lac one b idge seems o bebene icial o he ac i i y compa ed o a ee ca boxylic acid. Combina ions o 53 and 54 wi h e acycline e ealed syne gis ic e ec s agains he Te K-possessing s ain XU212. Compound 53, u he mo e, exhibi ed po en syne gis ic e ec s in combina ion wi h e y h omycin. Teasdale e al. (2012) isola ed six b omina ed di e penoids o he sphae odiene ype (55–60) om a membe o he genus Callophycus. The eby, compounds 59 and 57 we e only mode a ely ac i e, whe eas compounds 58 and 55 showed a MIC alue o 6.3 μg/mL and compounds 60 and 56 we e ac i e wi h a MIC alue o 1.6 μg/mL. The genus Callophycus was also he sou ce o eigh halogena ed me odi e penoids (61–68). All compounds showed mode a e ac i i y, excep compounds 63 (MIC: 1.4 μg/mL), 62 (MIC: 8 μg/mL), and 68 (MIC: 1.8 μg/mL), which exhibi ed p onounced e ec s (La oie e al., 2017). The s uc u al complexi y o his g oup o di e penoids de i es om he addi ion o a pa a-hyd oxybenzoic acid o he di e pene sca old ei he a he me hyl g oup a posi ion 8 (56) o a posi ion 9 (55). Fu he condensa ion o 56 leads o he benzo u an moie y o compounds 57–60, and 61–62, espec i ely. In e es ingly, he o ma ion o a dihyd opy an ing be ween he di e pene sca old and he pa a-hyd oxybenzoic acid moie y (as o compound 55) led o a ou - old lowe ac i i y, while he o ma ion o a benzo u an-connec ed sys em (60) did no al e he an ibac e ial e ec (compa ed o 56). Mo eo e , he o ma ion o a me hyl es e (61) as well as he oxygena ion o he p enyl moie y (as o compounds 57–59) dec eased he ac i i y. This e ec was less p onounced o he pe oxide (58), hough. 3.2.3. T i e penoids In his sec ion six cycloa ane- ype i e penoids, wo damma anes, as well as one lupane, one u sane, one oleane, and one a axas ane will bediscussed (Figu e4). Wea e e al. (2022) isola ed 18β-glycy he inic acid (69) om he oo s o a Glycy hiza sp. The compound exhibi ed ew e ec s bu lowe ed MRSA i ulence in i o. Mic ome ic acid (70) was isola ed by Khin e al. (2021) oge he wi h be ulinic acid (72) om Rosma inus o icinalis. The eby, 72 showed high ac i i y (MIC: 8 μg/mL) agains he communi y-associa ed s ain USA 300, whe eas 70 was only mode a ely ac i e. Chung e al. (2011, 2014) also isola ed be ulinic acid (72) oge he wi h α-amy in (71) om Callica pa a inosa, which was la e eclassi ied as Callica pa omen osa. Bo h compounds showed mode a e ac i i y, wi h subsequen mechanis ic assays e ealing p omising esul s agains a a ie y o bac e ial ansc ip ion mechanisms (Chung e al., 2014). The only wo i e pene glycosides (73 and 74) we e isola ed by Ga o e al. (2009) om Oncoba manii, FIGURE4 Chemical s uc u es o i e penoids wi h epo ed an i-MRSA ac i i y. Mo eno Ca denas and Çiçek 10.3389/ micb.2023.1234115 F on ie s in Mic obiology 07 on ie sin.o g which is now eg ouped in o he Camp os ylus genus, bo h showing comple e g ow h inhibi ion a 16 μg/mL. Un o una ely, no enough compound could beisola ed o he de e mina ion o MIC alues. Salam e al. (2021) isola ed 75 om he lea es o Cas anea sa i a, showing only mode a e an i-MRSA ac i i y. Howe e , u he s udies showed ha he i ulence was a enua ed by 75. Fi e cycloa ane i e penoids we e isola ed by Wang e al. (2013) om Aphanamixis g andi olia, now eclassi ied as Aphanamixis polys achya, o which ou compounds (76–79) we e mode a ely ac i e (wi h MIC alues anging om 25 o 50 μg/mL) and one compound (80) showed ema kable e ec s (MIC: 1.57 μg/mL). The eby no only he hyd oxy g oup in posi ion 3 seems o play an impo an ole o he ac i i y, bu also a second me hyl g oup a posi ion 4. 3.3. Phenolics The g oup o phenolics is di ided in o se en sec ions, o which some summa ize se e al smalle compound classes (in e ms o he numbe o compounds wi h an i-MRSA ac i i y). Sec ion 3.3.1, i.e., discusses 16 ca eic acid de i a i es, o which six a e chalcones, h ee a e benzylch omanes, and wo a e lignans. 3.3.1. Ca eic acid de i a i es The oo ba ks o Co dia gille ii yielded e ulaldehyd (81), which exhibi ed mode a e e ec s in a s udy by Okusa e al. (2014). Rosma inic acid (82) and i s me hyl es e (83) we e isola ed by Sab y e al. (2022) om he s em ba k o Co dia a icana. While 82 was only mode a ely ac i e (wi h a MIC alue o 31.25 μg/mL), he me hyla ed o m (83) showed p onounced e ec s (MIC: 7.81 μg/mL). Zuo e al. (2015) isola ed wo biphenyl compounds, 84 and 85, om Biancaea sappan, which was p e iously asc ibed o he genus Caesalpinia, in a bioac i i y-guided isola ion p ocedu e. Bo h compounds showed mode a e o low ac i i y bu demons a ed syne gis ic e ec s in combina ion wi h amikacin and gen amycin (Figu e5). Chan e al. (2012) isola ed ku a idin (86), a p enyla ed chalcone, om he adi ional Chinese medicial plan Sopho a la escens using high-speed coun e -cu en ch oma og aphy. The compound showed high ac i i y (MIC: 8 μg/mL) agains he e lux pump exp essing s ains RN4220 (mac olides) and SA-1199B ( luo oquinolones) and agains a ep esen a i e heal hca e-associa ed s ain (SA-ST239). Addi ional checkboa d s udies ound plen y o addi i e e ec s in combina ion wi h an ibio ics, sugges ing ha he an ibac e ial ac ion is no di ec ly ela ed o he e lux pump inhibi ion. Kim e al. (2017) FIGURE5 Chemical s uc u es o ca eic acid de i a i es wi h epo ed an i-MRSA ac i i y. Mo eno Ca denas and Çiçek 10.3389/ micb.2023.1234115 F on ie s in Mic obiology 08 on ie sin.o g isola ed licochalcone A (87) and E (88) om Glycy hiza in la a, also known as Chinese lico ice. Bo h compounds showed mode a e o high ac i i y (MIC: 10 o 20 μg/mL) agains six di e en s ains, e en pa ly su passing he e ec o he posi i e con ols. Lee e al. (2009) es ed he dihyd ochalcone phlo e in (89), which was ob ained om a compound lib a y. Wi h low oxici y and a MIC alue o 16 μg/mL, he au ho s sugges ha he ac i i y agains MRSA co ela es wi h he high a ini y o he β-ke oacyl-acyl ca ie po ein syn hase III (KASIII), a unc ional enzyme in he bac e ial a y acid biosyn hesis. Bocque e al. (2019) ex ac ed eigh di e en p enyla ed phenolic compounds om he emale in lo escences o Humulus lupulus, which a e used o bee b ewing. Xan hohumol (90) was signi ican ly ac i e wi h a MIC alue o 9.8 μg/mL, while desme hylxan hohumol (91) showed only mode a e ac i i y agains he es ed clinical isola es. Mo eo e , xan hohumol (90) displayed syne gis ic e ec s in combina ion wi h gen amycin, cip o loxacin, oxacillin, and i ampicin. Honokiol (92) and magnolol (93), wo lignans om he s em ba k o a non-speci ied membe o he genus Magnolia, which is used in adi ional Chinese and Japanese medicine, we e s udied by Chiu e al. (2021). Bo h compounds demons a ed high ac i i y agains MRSA (MIC: 10 μg/mL). Fu he in es iga ions showed ha bo h compounds ep essed he exp ession o mecA, a gene ha is impo an o he β-lac am esis ance o S. au eus. Addi ionally, bo h compounds dec eased he bio ilm o ma ion in a sub-MIC concen a ion, which may esul om ep essing bio ilm o ma ion ela ed genes. Zuo e al. (2014) isola ed h ee 3-benzylch oman de i a i es (94–96) om he hea wood o he Chinese d ug Caesalpinia sappan (now Biancaea sappan). The compounds showed low o mode a e ac i i y wi h MIC alues anging om 16 o 64 μg/ mL. Fu he s udies e ealed high syne gis ic e ec s o b azilin (94) wi h gen amycin, e imicin, and s ep omycin and o b azilein (95) wi h azi h omycin, gen amycin, and ce azidime, epec i ely. 3.3.2. Fla onoids The p esen sec ion discusses eigh la onols, ou la ones, h ee la anones, wo la ans, and one la anone (Figu e6). P enyla ed la onoids will bedeal wi h in he subsequen sec ion (3.3.3). Koagne e al. (2018) isola ed 97 and 98 oge he wi h wo alkaloids om C inum dis ichum, which was eclassi ied as C inum o na um. FIGURE6 Chemical s uc u es o la onoids wi h epo ed an i-MRSA ac i i y. Mo eno Ca denas and Çiçek 10.3389/ micb.2023.1234115 F on ie s in Mic obiology 09 on ie sin.o g Bo h compounds showed mode a e ac i i y agains a no u he speci ied MRSA s ain (Koagne e al., 2018). Alhad ami e al. (2020) pe o med a s uc u e-based in e se i ual sc eening, disco e ing he penicillin-binding p o ein 2a (PBP2a) as a po en ial a ge o hei la onoid da abase. PBP2a media es he an ibac e ial and an ibio ic-syne gis ic e ec o he es ed compounds. Subsequen ly, 23 di e en la onoids we e in es iga ed, o which que ce in (102, MIC: 62.5 μg/mL), apigenin (100, MIC: 31.25 μg/mL), ch ysin (101, MIC: 15.62 μg/mL), and hespe e in (99, MIC: 31.25 μg/mL) showed he highes ac i i y agains he me hicillin- esis an s ain ATCC 33591. Because he ac i i y nega i ely co ela ed wi h he numbe o ee hyd oxy g oups he au ho s concluded ha a lowe pola i y is bene icial o he posi i e e ec s. Pang e al. (2022) isola ed mo in (103) om Mo us alba wi h a low ac i i y (100 μg/mL). Lee e  al. (2009) pe o med a ecep o -o ien ed pha macopho e-based in silico sc eening o new inhibi o s o he bac e ial a y acid syn hase (FAS), e ealing 3,6-dihyd oxy la one (104) as a po en compound agains MRSA (wi h a MIC alue o 16 μg/mL). Commipho a peduncula a, a adi ionally used medicinal plan species common in A ica, A abia, and he Indian subcon inen , is he sou ce o dihyd okaemp e ol (105), which displayed mode a e ac i i y agains a clinical isola e (Tajuddeen e al., 2014). Oluwa uyi e al. (2004) in es iga ed 106 om Rosma inus o icinalis agains h ee di e en d ug- esis an s ains. The eby, he highes ac i i y (16 μg/ mL) was ound agains he e acycline e lux pump possessing s ain. Nzogong e  al. (2018) isola ed 107 and 110, wo low- o mode a ely ac i e glycosyla ed la onoids om Disso is senegambiensis, which was eg ouped in o he genus An he o oma, along wi h ou i e penoids and i e annins. Two la anonol hamnosides (108 and 109) we e isola ed by An e al. (2011) om Hype icum japonicum and es ed agains 10 me hicillin- esis an and one me hicillin-sensi i e s ain. While 108 was a ec ing all es ed s ains, 109 was only inhibi ing h ee s ains. Howe e , MIC alues o bo h compounds we e only a a mode a e o low le el ( anging om 32 o 64 μg/mL). The glycosyla ed la onoids wi h he highes ac i i y we e isola ed om he lea es o Pla anus occiden alis, he Ame ican sycamo e (111–114) (Ib ahim e  al., 2009). All ou compounds display kaemp e ol 3-O-dicouma oyl hamnosides, wi h di e en geome ic isome ism o he couma oyl moie ies. The eby, he de i a i e bea ing wo ans-couma oyl moie ies (111) exhibi ed he lowes ac i i y (MIC alue o 10 μg/mL), while wo cis-couma oyl moie ies (114) led o a MIC alue o 0.6 μg/mL and hus o a e y FIGURE7 Chemical s uc u es o p enyla ed la onoids wi h epo ed an i-MRSA ac i i y. Mo eno Ca denas and Çiçek 10.3389/ micb.2023.1234115 F on ie s in Mic obiology 16 on ie sin.o g TABLE1 O e iew on addi i e and syne gis ic e ec s wi h exis ing an ibio ics indica ed by FICI alues and combined MIC alues, espec i ely. No. MRSA s ain Amikacin Ampicillin Azi h omycin Ce azidime Cip o loxacin Gen amicin Le o loxacin No loxacin Oxacillin Addi ional an ibio ics Re e ences 4 MRSA-011 0.5 Zeng e al. (2022) MRSA-003 0.375 5 MRSA-011 0.5 Zeng e al. (2022) MRSA-003 0.5 7 ATCC 33591 E hidium b omide: 7.8 μg/mL (2×) Zuo e al. (2011) 9 OMS 7 0.625 0.5 Yu e al. (2005) MRSA 004 0.375 0.5 Zuo e 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 e 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 e al. (2019) 46 ATCC 43300 0.25 μg/mL (256×)/0.125 Me openem: 0.094 De weile e al. (2020) Vancomycin: 0.625 (Con inued) Mo eno Ca denas and Çiçek 10.3389/ micb.2023.1234115 F on ie s in Mic obiology 17 on ie sin.o g No. MRSA s ain Amikacin Ampicillin Azi h omycin Ce azidime Cip o loxacin Gen amicin Le o loxacin No loxacin Oxacillin Addi ional an ibio ics Re e ences 53 XU212 Te acycline: 64 μg/ mL (2×) Oluwa uyi e al. (2004) RN4220 E y h omycin: 32 μg/mL (8×) SA1199B 32 μg/mL (1×) E hidium b omide: 8 μg/mL (2×) 54 XU212 Te acycline: 32 μg/ mL (4×) Oluwa uyi e al. (2004) RN4220 E y h omycin: 256 μg/mL (1×) SA1199B 32 μg/mL (1×) 84 MRSA 0.313–1 0.5–1 0.75–1.5 Ce azolin: 0.625–2 Zuo e al. (2015) 85 MRSA 0.078–1 0.313–1 Amoxicillin: 0.625–2 Zuo e al. (2015) 90 T28.1 0.49–1 0.14–1 0.28–0.75 Ri ampicin: 0.25–0.75 Bocque e al. (2019) 91 T28.1 0.38–1.5 0.03–0.28 0.5–0.76 Ri ampicin: 1–5 Bocque e al. (2019) 94 MRSA 0.25–2 0.25–1 E imicin: 0.375–0.75 Zuo e al. (2014) S epomycin: 0.25–1 95 MRSA 0.47–0.75 0.188–2 0.375–1 Penicillin: 0.625–1 Zuo e al. (2014) 96 MRSA 0.625–1 0.5–1 0.75–1.5 Ce azolin: 0.75–2 Zuo e al. (2014) 108 MRA 004 0.5 1.5 0.25 0.312 An e 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 Te acycline: 0.14 Aelenei e al. (2020) (Con inued) TABLE1 (Con inued) Mo eno Ca denas and Çiçek 10.3389/ micb.2023.1234115 F on ie s in Mic obiology 18 on ie sin.o g TABLE1 (Con inued) No. MRSA s ain Amikacin Ampicillin Azi h omycin Ce azidime Cip o loxacin Gen amicin Le o loxacin No loxacin Oxacillin Addi ional an ibio ics Re e ences 122 MRSA 1903 0.625 Na á ilo á e al. (2016) MRSA 3202 0.375 MRSA 62097 1.008 MRSA 67755 0.508 MRSA 1679 0.266 123 MRSA 1903 0.266 Na á ilo á e 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 Te acycline: 0.38 Aelenei e al. (2020) 128 ATCC 29213 0.135 Meenu e al. (2021) 140 ATCC 1708 Me openem: 0.375 Kuma ihamy e al. (2022) Vancomycin: 1 187 ATCC 33591 0.5 0.5 Lee e 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 Ri ampicin: 2.2–6 Bocque e al. (2019) Mo eno Ca denas and Çiçek 10.3389/ micb.2023.1234115 F on ie s in Mic obiology 19 on ie sin.o g po en ia ing he e ec o a compound bu a e also needed o inc ease he compounds’ bioa ailabili y and physical p ope ies. Fo example, phenolic compounds, such as la onoids, a e apidly elimina ed, whe eas many e penoids show low solubili y in aqueous solu ions. He e, bio echnological app oaches could gua an ee p o ision o high- pu i y compounds ha a e p oduced in bio eac o s. Howe e , his equi es unde s anding o he biosyn he ic pa hways leading o he na u al p oduc o in e es , which cu en ly is no he case o many plan species (Po as e al., 2021). He e, compu a ional echniques such as genome mining and he use o genomic and ansc ip omic da abases show possible app oaches o enable he syn hesis o na u al p oduc s in mic oo ganisms. Al e na i ely, plan species such as Nico iana ben hamiana could se e as p oducing o ganisms, being mo e closely ela ed and hus mo e sui able o c ea e, e.g., glycosyla ed na u al p oduc s (Molina-Hidalgo e al., 2021). 5. Summa y and conclusion In his e iew a o al o 223 plan na u al p oduc s om mo e han 20 di e en compound classes a e p esen ed and discussed. Though mos o he epo ed compounds display mode a e e ec s, wi h ac i i ies anging om 10 o 50 μg/mL, a ew excep ions ac a low o e en submic omola concen a ions. Two such compounds a e he sesqui e pene lac ones pa henolide (24) and lac upic in (25), bo h showing a MIC alue o 0.16 μg/mL. In addi ion, he subclass o ace ophenone sesqui e penes p esen a se o in e es ing candida es, wi h ou compounds displaying p onounced e ec s (26–28, 31). Simila ly, he subclass o me odi e penes, which also o igina e om wo di e en biosyn he ic pa hways, yield se e al highly ac i e cons i uen s (56, 60, 63, 68), wi h MIC alues be ween 1.4 and 1.8 μg/ mL. Fu he po en di e penes we e ound in he class o abie anes (48, 49) and sphae odienes (38, 40), espec i ely. O no e, o compound 38 MIC alues o 0.25–1 μg/mL agains i e di e en s ains ha e been de e mined. The class o i e penoids only e ealed one in e es ing compound (80), as did he class o alkaloids (6). Howe e , many o he epo ed alkaloids displayed syne gis ic e ec s wi h exis ing an ibio ics, which esul om he inhibi ion o he bac e ial e lux pump. (Table1) S ong syne gis ic e ec s (wi h cip o loxacin, gen amicin, oxacillin, and e acycline) we e also epo ed o he p enyla ed la ones mo usin (116) and kuwanon G (127). Likewise, axi olin 7-O-α-L- hamnopy anoside (108), displayed syne gism wi h ce azidime and le o loxacin, bu was only sligh ly ac i e alone. Th ee la onol dicouma oyl hamnosides (112–114), in con as , exhibi ed p onounced e ec s wi h MIC alues o 1.7–0.6 μg/mL. O he in e es ing phenolic compounds we e ound in he classes o iso la onoids (132), xan hones (170, 171), an h anoids (187, 191), and abo e all, in he class o phlo oglucinols. He e, se e al compounds exhibi ed ema kable e ec s, such as lupulone (194, MIC alues o 0.6–1.2 μg/mL), i esinol (203, MIC: 0.31 μg/mL), hodomy one (204, MIC: 0.5 μg/mL), aspidinol (205, MIC: 0.5–2 μg/mL), and hype o in (206, MIC: 0.5–2 μg/mL), hus ende ing phlo oglucinol de i a i es he mos p omising compound class o u he d ug de elopmen . Finally, wo a he unusual plan na u al p oduc s ha e been epo ed, which we e he cyclopen apy an 213 (wi h a MIC alue o 1 μg/mL) and he mac olide neu ymenolide A (214, wi h an IC 50 alue o 0.77 μg/mL). In summa y, se e al compounds wi h p onounced and/o syne gis ic e ec s agains Me hicillin- esis an S aphylococcus au eus ha e been isola ed om plan species. Some o hem e en showed MIC alues compa able o he es ablished an ibio ics ancomycin, dap omycin, igecycline, and linezolid, espec i ely (Ni edi ha and Suja ha, 2015). S ill, none o he men ioned compounds managed o p oceed owa d a comme cial an ibio ic d ug. Whe he he es ic ed ac i i y o only a ew ou o se e al s ains o hei limi ed a ailabili y we e he eason o no u he de elop he espec i e compounds could no bede e mined. In he la e case, he u u e will show i eme ging bio echnological me hods will help o p o ide highe amoun s o na u al p oduc s o subsequen clinical s udies o semi-syn he ic and echnological modi ica ions. In addi ion, mo e comp ehensi e app oaches, e.g., s udies wi h en iched ex ac s o de ined ac ions, may p esen an al e na i e o some s ages in d ug de elopmen . And las bu no leas , e hnopha macological esea ch will ha e o adap o in e na ional con en ions, e.g., he Nagoya p o ocol, aking hem as wha hey a e, namely measu es o p o ec biodi e si y and na u al he i age and no obs acles in d ug disco e y. Au ho con ibu ions CMC conduc ed he li e a u e sea ch, o ganized he da a, and w o e he o iginal d a . SÇ was e iewing, w i ing, and edi ing he o iginal d a , supe ising he wo k, and acqui ing he unding o publica ion. All au ho s con ibu ed o he a icle and app o ed he submi ed e sion. Funding The au ho s acknowledged inancial suppo by he DFG wi hin he unding p og am “Open Access-Publika ionskos en”. Con lic o in e es The au ho s decla e ha he esea ch was conduc ed in he absence o any comme cial o inancial ela ionships ha could becons ued as a po en ial con lic o in e es . Publishe ’s no e All claims exp essed in his a icle a e solely hose o he au ho s and do no necessa ily ep esen hose o hei a ilia ed o ganiza ions, o hose o he publishe , he edi o s and he e iewe s. Any p oduc ha may be e alua ed in his a icle, o claim ha may be made by i s manu ac u e , is no gua an eed o endo sed by he publishe . Supplemen a y ma e ial The Supplemen a y ma e ial o his a icle can be ound online a : h ps://www. on ie sin.o g/a icles/10.3389/ micb.2023.1234115/ ull#supplemen a y-ma e ial Mo eno Ca denas and Çiçek 10.3389/ micb.2023.1234115 F on ie s in Mic obiology 20 on ie sin.o g Re e ences Ab eu, A. C., McBain, A. J., and Simões, M. (2012). Plan s as sou ces o new an imic obials and esis ance-modi ying agen s. Na . P od. Rep. 29, 1007–1021. doi: 10.1039/c2np20035j Aelenei, P., Rimbu, C. M., Ho hogea, C. E., Lobiuc, A., Neagu, A.-N., Dunca, S. I., e al. (2020). P enyla ed phenolics as p omising candida es o combina ion an ibac e ial he apy: mo usin and kuwanon G. 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