MexAB-OprM-specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 1: discovery and early strategies for lead optimization

…, M Ohtsuka, H Kawato, K Yoshida, Y Yokomizo…

Index: Nakayama, Kiyoshi; Ishida, Yohei; Ohtsuka, Masami; Kawato, Haruko; Yoshida, Ken-Ichi; Yokomizo, Yoshihiro; Hosono, Shigeru; Ohta, Toshiharu; Hoshino, Kazuki; Ishida, Hiroko; Yoshida, Kumi; Renau, Thomas E.; Leger, Roger; Zhang, Jason Z.; Lee, Ving J.; Watkins, William J. Bioorganic and Medicinal Chemistry Letters, 2003 , vol. 13, # 23 p. 4201 - 4204

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Citation Number: 59

Abstract

The identification of a series of compounds that specifically inhibit efflux by the MexAB-OprM pump system in Pseudomonas aeruginosa is described. Synthesis and in vitro structure– activity relationships (SARs) are outlined. Early leads lacked activity in animal models, and efforts to improve solubility and reduce serum protein binding by the introduction of polar groups are discussed.