WARREN MS, LEE JC, LEE A, HOSHINO K, ISHIDA H, LOMOVSKAYA O; Interscience Conference on Antimicrobial Agents and Chemotherapy.
Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2000 Sep 17-20; 40: 207.
Microcide Pharmaceuticals, Inc., Mountain View, CA
MC-207,110 has recently been identified in high-throughput screening of small molecule libraries as an inhibitor of the three multi-drug resistance (MDR) pumps (MexAB-OprM, MexCD-OprJ and MexEF-OprN) that belong to the RND family of transporters and contribute to fluoroquinolone resistance in clinical isolates of Pseudomonas aeruginosa. This compound also possesses inhibitory activity against RND MDR pumps from other bacterial species, such as Escherichia coli, Salmonella typhimurium and Haemophilus influenzae. Herein we present evidence that MC-207,110 is also a substrate of RND pumps, based on the results of whole-cell accumulation experiments. In mutants of P. aeruginosa overexpressing each of the three Mex pumps, the initial rate of uptake of MC-207,110 was significantly less than in a mutant lacking these pumps. After treatment with the protonophore CCCP, which dissipates the proton gradient essential for efflux activity, all strains accumulated MC-207,110 at the same rate, indicating that MC-207,110 is effluxed from P. aeruginosa by the Mex pumps. These data provide additional evidence that MC-207,110 interacts directly with pump proteins. Structural analogs of MC-207,110 were able to inhibit efflux of MC-207,110. Interestingly, none of the known substrates of the MexAB-OprM pump tested so far (nalidixic acid, chloramphenicol, trimethoprim, erythromycin, tetracycline, carbenicillin) competed with MC-207,110 for efflux by this pump.KEYWORDS: Efflux pumps; Inhibitors; Pseudomonas
Publication Types:
Keywords:
- Dipeptides
- Drug Resistance, Multiple
- Escherichia coli
- Escherichia coli Proteins
- Membrane Transport Proteins
- Pseudomonas aeruginosa
- antagonists & inhibitors
- phenylalanine arginine beta-naphthylamide
Other ID:
UI: 102247849
From Meeting Abstracts