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

Piddock, Laura J.V., Garvey, Mark I., Rahman, M. Mukhlesur and Gibbons, Simon (2010) Natural and synthetic compounds such as trimethoprim behave as inhibitors of efflux in Gram-negative bacteria. Journal of Antimicrobial Chemotherapy, 65 (6). pp. 1215-1223. ISSN 0305-7453

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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,pharmacology,microbiology (medical),infectious diseases,pharmacology (medical) ,/dk/atira/pure/subjectarea/asjc/3000/3004
Faculty \ School: Faculty of Science > School of Pharmacy
Related URLs:
Depositing User: LivePure Connector
Date Deposited: 15 Jul 2020 23:39
Last Modified: 15 Jul 2020 23:39
URI: https://ueaeprints.uea.ac.uk/id/eprint/76129
DOI: 10.1093/jac/dkq079

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