Microbial fermentation-derived inhibitors of efflux-pump-mediated drug resistance.
A library of 85000 microbial fermentation extracts was screened for inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa and Candida albicans. New compounds EA-371alpha and EA-371delta 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 CDRI 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.
Lee
M D
MD
Microcide Pharmaceuticals, Inc., Mountain View, CA 94043, USA. mlee@microcide.com
Galazzo
J L
JL
Staley
A L
AL
Lee
J C
JC
Warren
M S
MS
Fuernkranz
H
H
Chamberland
S
S
Lomovskaya
O
O
Miller
G H
GH
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001425:Bacterial Outer Membrane Proteins / Q000037:antagonists & inhibitors*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D004352:Drug Resistance, Microbial; D005285:Fermentation; D005656:Fungal Proteins / Q000037:antagonists & inhibitors; D026901:Membrane Transport Proteins
D018528:ATP-Binding Cassette Transporters; D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; C094693:CDR1 protein, Candida albicans; D002352:Carrier Proteins; D005656:Fungal Proteins; D026901:Membrane Transport Proteins; C118598:MexA protein, Pseudomonas aeruginosa; C118597:MexB protein, Pseudomonas aeruginosa; C105708:OprN protein, Pseudomonas aeruginosa