another recent publication.......
Antimicrob Agents Chemother 1999 Jun;43(6):1340-6
Use of a genetic approach to evaluate the consequences of inhibition of
efflux pumps in Pseudomonas aeruginosa.
Lomovskaya O, Lee A, Hoshino K, Ishida H, Mistry A, Warren MS, Boyer E, Chamberland S, Lee VJ
Microcide Pharmaceuticals Inc., Mountain View, California 94043, USA. olga@microcide.com
Drug efflux pumps in Pseudomonas aeruginosa were evaluated as potential targets for antibacterial therapy. The potential
effects of pump inhibition on susceptibility to fluoroquinolone antibiotics were studied with isogenic strains that overexpress or
lack individual efflux pumps and that have various combinations of efflux- and target-mediated mutations. Deletions in three
efflux pump operons were constructed. As expected, deletion of the MexAB-OprM efflux pump decreased resistance to
fluoroquinolones in the wild-type P. aeruginosa (16-fold reduction for levofloxacin [LVX]) or in the strain that overexpressed
mexAB-oprM operon (64-fold reduction for LVX). In addition to that, resistance to LVX was significantly reduced even for
the strains carrying target mutations (64-fold for strains for which LVX MICs were >4 microg/ml). We also studied the
frequencies of emergence of LVX-resistant variants from different deletion mutants and the wild-type strain. Deletion of
individual pumps or pairs of the pumps did not significantly affect the frequency of emergence of resistant variants (at 4x the
MIC for the wild-type strain) compared to that for the wild type (10(-6) to 10(-7)). In the case of the strain with a triple
deletion, the frequency of spontaneous mutants was undetectable (<10(-11)). In summary, inhibition of drug efflux pumps
would (i) significantly decrease the level of intrinsic resistance, (ii) reverse acquired resistance, and (iii) result in a decreased
frequency of emergence of P. aeruginosa strains highly resistant to fluoroquinolones in clinical settings. |
