Natural and synthetic compounds such as trimethoprim behave as inhibitors of efflux in Gram-negative bacteria.

Piddock, L.J.V., Garvey, M.I., Rahman, M.M. and Gibbons, S. (2010) Natural and synthetic compounds such as trimethoprim behave as inhibitors of efflux in Gram-negative bacteria. Journal of Antimicrobial Agents and Chemotherapy, 65 (6). pp. 1215-1223. 10.1093/jac/dkq079 .

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DOI: 10.1093/jac/dkq079

Abstract

Objectives We hypothesized that small heterocyclic or nitrogen-containing compounds could act as RND efflux pump inhibitors (EPIs). To ascertain possible EPIs, we sought to identify compounds that synergized with substrates of RND efflux pumps for wild-type bacteria and those that overexpress an efflux pump, but had no synergistic activity against strains in which a gene encoding a component of the AcrAB-TolC efflux pump had been inactivated. Methods Twenty-six compounds plus l-phenylalanyl-l-arginyl-β-naphthylamide (PAβN) and carbonyl cyanide m-chlorophenylhydrazone (CCCP) were screened by bioassay to identify compounds that synergized with ciprofloxacin for a range of Enterobacteriaceae and Pseudomonas aeruginosa. The MICs of ciprofloxacin, tetracycline, chloramphenicol, erythromycin and ethidium bromide ± synergizing compounds were determined, and the ability to inhibit the efflux of Hoechst 33342 was measured. Results Two compounds, trimethoprim and epinephrine, consistently showed synergy with antibiotics for most strains. The combinations did not show synergy for Salmonella enterica serovar Typhimurium in which the AcrAB-TolC efflux pump was inactive. Both compounds inhibited the efflux of Hoechst 33342. Conclusions Two compounds, trimethoprim and epinephrine, which are already licensed for use in man, may warrant further analysis as EPIs. The combination of trimethoprim with another antibiotic is a well-used combination in anti-infective chemotherapy, and so combination with another agent, such as a quinolone, may be a viable option and further studies are now required.

Item Type:Article
Uncontrolled Keywords:AcrAB-TolC antibiotic resistance EPIs
Departments, units and centres:Department of Pharmaceutical and Biological Chemistry > Centre for Pharmacognosy and Phytotherapy
ID Code:1594
Journal or Publication Title:Journal of Antimicrobial Agents and Chemotherapy
Deposited By:Library Staff
Deposited On:24 Jun 2010 10:49
Last Modified:18 Nov 2011 16:48

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