A new plant-derived antibacterial is an inhibitor of efflux pumps in Staphylococcus aureus

Winnie K P Shiu, John P Malkinson, M Mukhlesur Rahman, Jonathan Curry, Paul Stapleton, Mekala Gunaratnam, Stephen Neidle, Shazad Mushtaq, Marina Warner, David M Livermore, Dimitrios Evangelopoulos, Chandrakala Basavannacharya, Sanjib Bhakta, Bryan D Schindler, Susan M Seo, David Coleman, Glenn W Kaatz, Simon Gibbons

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An in-depth evaluation was undertaken of a new antibacterial natural product (1) recently isolated and characterised from the plant Hypericum olympicum L. cf. uniflorum. Minimum inhibitory concentrations (MICs) were determined for a panel of bacteria, including: meticillin-resistant and -susceptible strains of Staphylococcus aureus, Staphylococcus epidermidis and Staphylococcus haemolyticus; vancomycin-resistant and -susceptible Enterococcus faecalis and Enterococcus faecium; penicillin-resistant and -susceptible Streptococcus pneumoniae; group A streptococci (Streptococcus pyogenes); and Clostridium difficile. MICs were 2-8mg/L for most staphylococci and all enterococci, but were ≥16mg/L for S. haemolyticus and were >32mg/L for all species in the presence of blood. Compound 1 was also tested against Gram-negative bacteria, including Escherichia coli, Pseudomonas aeruginosa and Salmonella enterica serovar Typhimurium but was inactive. The MIC for Mycobacterium bovis BCG was 60mg/L, and compound 1 inhibited the ATP-dependent Mycobacterium tuberculosis MurE ligase [50% inhibitory concentration (IC50)=75μM]. In a radiometric accumulation assay with a strain of S. aureus overexpressing the NorA multidrug efflux pump, the presence of compound 1 increased accumulation of (14)C-enoxacin in a concentration-dependent manner, implying inhibition of efflux. Only moderate cytotoxicity was observed, with IC50 values of 12.5, 10.5 and 8.9μM against human breast, lung and fibroblast cell lines, respectively, highlighting the potential value of this chemotype as a new antibacterial agent and efflux pump inhibitor.
Original languageEnglish
Pages (from-to)513-8
Number of pages6
JournalInternational Journal of Antimicrobial Agents
Issue number6
Publication statusPublished - Dec 2013

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