Session: Inhibitors of Bacterial and Fungal Efflux Pumps
Location:
Exhibit Hall
Session Date:
Monday, 9/27/99
Session Time:
3:00 pm - 4:30 pm
Inhibitors of Fungal Efflux Pumps
O. Lomovskaya1, M. Warren1, A. Mistry1, A. Staley1, J. Galazzo1, H.
Fuernkranz1, M. Lee1, G. Miller1, D. Sanglard2
1Microcide Pharmaceuticals, Inc.: Mountain View, CA; 2Inst. of Microbiol.:
Lausanne, Switzerland
Multi-Drug Resistance (MDR) pumps in C. albicans modulate their susceptibility to
many antifungal agents. These pumps may also be implicated as the cause of the high
intrinsic non-susceptibility of many Candida species to azoles. We have screened
synthetic compounds and natural products for inhibitors of CDR-type pumps (ABC
transporters) in C. albicans and C. glabrata. Several chemical types of fungal efflux
pump inhibitors (FEPIs) were identified. Their specific mode-of-action was verified by
secondary assays that demonstrated that: 1) FEPIs reversed pump-mediated resistance
to antifungal agents active against different cellular targets (azoles, terbinafine, rhodamine
6G) and did not potentiate antifungals that are not substrates of efflux pumps
(amphotericin B); 2) FEPIs did not have significant activity against containing deletions of
efflux pumps genes; 3) FEPIs completely reversed resistance in recombinant S.
cerevisiae strains overexpressing efflux pumps from C. albicans or C. glabrata; and 4)
FEPIs increased intracellular accumulation of the efflux pump substrate Rhodamine 6G
and inhibited its efflux from preloaded cells. These inhibitors did not have significant
activity against MDR-pumps of the Major Facilitator family (BenR from C. albicans and
C. glabrata), however they were active against multiple CDR-pumps in multiple
Candida species. A single compound can reverse CDR-mediated azole resistance in C.
albicans (64-128-fold reduction in MIC of fluconazole [FLU] or SCH-56592 [SCH])
and reduce intrinsic resistance in C. glabrata (8-16-fold reduction in MIC of FLU or
SCH). Thus, broad-spectrum FEPIs may significantly enhance the clinical efficacy of
azoles against various Candida species. |
