title: A new plant-derived antibacterial is an inhibitor of efflux pumps in Staphylococcus aureus.
abstract: 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 2-8 mg/L for most staphylococci and all enterococci, but were ≥16 mg/L for S. haemolyticus and were >32 mg/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 60 mg/L, and compound 1 inhibited the ATP-dependent Mycobacterium tuberculosis MurE ligase [50% inhibitory concentration (IC(50)) = 75 μM]. 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 8.9 μM 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.
authors.affiliation: Department of Pharmaceutical and Biological Chemistry, UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK.
authors.forename: Winnie K P
authors.initials: WK
authors.lastname: Shiu
authors.forename: John P
authors.initials: JP
authors.lastname: Malkinson
authors.forename: M Mukhlesur
authors.initials: MM
authors.lastname: Rahman
authors.forename: Jonathan
authors.initials: J
authors.lastname: Curry
authors.forename: Paul
authors.initials: P
authors.lastname: Stapleton
authors.forename: Mekala
authors.initials: M
authors.lastname: Gunaratnam
authors.forename: Stephen
authors.initials: S
authors.lastname: Neidle
authors.forename: Shazad
authors.initials: S
authors.lastname: Mushtaq
authors.forename: Marina
authors.initials: M
authors.lastname: Warner
authors.forename: David M
authors.initials: DM
authors.lastname: Livermore
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Evangelopoulos
authors.forename: Chandrakala
authors.initials: C
authors.lastname: Basavannacharya
authors.forename: Sanjib
authors.initials: S
authors.lastname: Bhakta
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Schindler
authors.forename: Susan M
authors.initials: SM
authors.lastname: Seo
authors.forename: David
authors.initials: D
authors.lastname: Coleman
authors.forename: Glenn W
authors.initials: GW
authors.lastname: Kaatz
authors.forename: Simon
authors.initials: S
authors.lastname: Gibbons
mesh_terms: D000900:Anti-Bacterial Agents / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D020902:Hypericum / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors*; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010936:Plant Extracts; C075040:NorA protein, Staphylococcus
keywords: Hypericum olympicum; MurE ligase; Olympicin A; Staphylococcus aureus