Microbial fermentation-derived inhibitors of efflux-pump-mediated drug resistance

Abstract A library of 85 000 microbial fermentation extracts was screened for inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa and Candida albicans . New compounds EA-371α and EA-371δ were isolated and demonstrated to be potent and specific inhibitors of the MexAB–OprM pump in P. aeruginosa . Two series of fungal metabolites, enniatins and beauvericins, were found to be ubiquitous and potent inhibitors of ABC transporters. Milbemycins were rediscovered as potent inhibitors of the CDR1 pump in C. albicans , and demonstrated to potentiate effectively the antifungal activity of fluconazole and SCH-56592 against a wide variety of Candida clinical isolates.