MF-EA371-a and MF-EA371-D, Novel Bacterial Efflux Pump Inhibitors from Microbial Fermentation
J. C. LEE1, J. L. GALAZZO1, T. IANIRO1, M. S. WARREN1, R. J. CANO2, S. CHAMBERLAND1, O. LOMOVSKAYA1, M. D. LEE1
1Microcide Pharmaceuticals, Inc., Mountain View, CA; 2California Polytechnic State Univ., San Luis Obispo, CA
Presentation Number: 1499
The continuous and indiscriminant use of antibiotics has selected bacterial populations that are resistant to many antibiotics. One of the mechanisms of resistance is by decreasing the antibiotic concentration inside the bacterial cells by antibiotic efflux. Three efflux pumps in Pseudomonas aeruginosa, MexAB-OprM, MexCD-OprJ, and MexEF-OprN, contribute to its clinical resistance against a variety of antibiotics [Li, X.-Z., Livermore, D. M., & Nikaido, H., Antimicrobial Agents & Chemotherapy, 1994 38(8), 1732-1741; Lawrence, L. E. & Barrett J. F., Exp. Opin. Invest. Drugs (1998) 7(2), 199-217]. The fermentation of MF-EA-371-NS1, a new strain of Streptomyces closely related to Streptomyces vellosus, produces two novel P. aeruginosa MexAB-OprM-specific efflux pump inhibitors, compounds MC-510,051 (MF-EA-371-alpha) and MC-510,050 (MF-EA-371-delta). Their chemical structures, elucidated by NMR and mass spectral data, were found to be O-sulfates of Benastatins B and A, respectively. In contrast, Benastatins A or B do not have significant efflux pump inhibitory activity. Media improvement studies to increase the titer of these new compounds, their isolation and structure determination, and their efflux pump inhibitory activities will be presented.
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