Expression of homologous RND efflux pump genes is dependent upon AcrB expression: implications for efflux and virulence inhibitor design.
Bottom Line: When two or three acr genes were inactivated, the mutants had further reduced efflux, altered susceptibility to antimicrobials (including increased susceptibility to some, but conversely and counterintuitively, decreased susceptibility to some others) and were more attenuated in the tissue culture model than mutants lacking single pumps were.These data indicate that it is critical to understand which pumps an inhibitor is active against and the effect of this on the expression of homologous systems.For some antimicrobials, an inhibitor with activity against multiple pumps will have a greater impact on susceptibility, but an unintended consequence of this may be decreased susceptibility to other drugs, such as aminoglycosides.
Affiliation: Antimicrobials Research Group, School of Immunity and Infection, College of Medical and Dental Sciences, and Institute of Microbiology and Infection, The University of Birmingham, Birmingham B15 2TT, UK.Show MeSH
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Mentions: We previously showed that the inactivation of acrB led to an increased accumulation of the dye Hoechst 33342.20 Compared with SL1344, the inactivation of acrD (L132) or acrF (L131) or the inactivation of both acrD and acrF (L1395) did not significantly alter the accumulation of Hoechst 33342 (Figure 2). However, mutants with inactivation of acrB and another acr gene [acrBD (L1297) or acrBF (L646)] accumulated less Hoechst 33342 than the acrB mutant. The acrBDF mutant (L1405) accumulated the highest level of Hoechst 33342, indicating the lowest level of efflux. Accumulation of the fluoroquinolone antibiotic norfloxacin showed a similar pattern, although the acrB mutant accumulated a higher concentration than the acrBDF mutant (Figure 3).Figure 2.
Affiliation: Antimicrobials Research Group, School of Immunity and Infection, College of Medical and Dental Sciences, and Institute of Microbiology and Infection, The University of Birmingham, Birmingham B15 2TT, UK.