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J Antimicrob Chemother. 2010 Jun;65(6):1215-23. doi: 10.1093/jac/dkq079. Epub 2010 Mar 19.

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

Author information

1
Antimicrobial Agents Research Group, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK. l.j.v.piddock@bham.ac.uk

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-beta-naphthylamide (PAbetaN) 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.

PMID:
20304975
DOI:
10.1093/jac/dkq079
[Indexed for MEDLINE]

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