A structure–activity relationship study of phenyl sesquiterpenoids on efflux inhibition against Staphylococcus aureus
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Sixteen natural acetophenone sesquiterpene derivatives were isolated from Ferula ferulioides and 11 synthetic acetophenone sesquiterpene analogues were evaluated to explore the structure–activity relationships (SARs) on their antibacterial activities against a panel of bacteria including drug-resistant Staphylococcus aureus. The minimum inhibitory concentration (MIC) values of the compounds were in the range of 0.5–128 mg/L. Preliminary SAR studies showed that subtle modifications on both the 2’,4’-dihydroxyphenyl moiety and the side chain reduced their activity against drug-resistant S. aureus. All of the compounds that showed no or only weak direct antibacterial activity were tested for their efflux inhibitory effects, among which four compounds showed significant efflux inhibition against drug-resistant strains. Natural product 14 showed significant inhibitory effects for EtBr efflux in strain SA1199B, which has reduced susceptibility to fluoroquinolones by efflux. Compounds 5, 14 and F-3 moderately inhibited EtBr efflux in the macrolide-resistant strain RN4220 and compound 13 moderately inhibited efflux in an MRSA and effluxing tetracycline-resistant strain.
KeywordsFerula ferulioides Acetophenone derivatives Structure–activity relationships Drug-resistant Staphylococcus aureus Efflux pump inhibition
This work was supported by an NSFC grant (21172041) Royal Society International Joint Project (Sino-UK Joint Project, JP091083/NSFC81011130165). We also thank support by the Mindao Project for medical graduate students of Fudan University (MDJH2012010).
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Conflict of interest
The authors declare that they have no conflict of interest.
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