Journal
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
Volume 68, Issue 7, Pages 1551-1557Publisher
OXFORD UNIV PRESS
DOI: 10.1093/jac/dkt069
Keywords
antibiotic resistance; efflux inhibitors; phenothiazines
Funding
- Medical Research Council (MRC) [G0801977]
- Medical Research Council [G0801977] Funding Source: researchfish
- MRC [G0801977] Funding Source: UKRI
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The transcriptional activator RamA regulates production of the multidrug resistance efflux AcrABTolC system in several Enterobacteriaceae. This study investigated factors that lead to increased expression of ramA. In order to monitor changes in ramA expression, the promoter region of ramA was fused to a gfp gene encoding an unstable green fluorescence protein (GFP) on the reporter plasmid, pMW82. The ramA reporter plasmid was transformed into Salmonella Typhimurium SL1344 and a acrB mutant. The response of the reporter to subinhibitory concentrations of antibiotics, dyes, biocides, psychotropic agents and efflux inhibitors was measured during growth over a 5 h time period. Our data revealed that the expression of ramA was increased in a acrB mutant and also in the presence of the efflux inhibitors phenylalanine-arginine--naphthylamide, carbonyl cyanide m-chlorophenylhydrazone and 1-(1-naphthylmethyl)-piperazine. The phenothiazines chlorpromazine and thioridazine also increased ramA expression, triggering the greatest increase in GFP expression. However, inducers of Escherichia coli marA and soxS and 12 of 17 tested antibiotic substrates of AcrABTolC did not induce ramA expression. This study shows that expression of ramA is not induced by most substrates of the AcrABTolC efflux system, but is increased by mutational inactivation of acrB or when efflux is inhibited.
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