title: MexAB-OprM-specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 1: discovery and early strategies for lead optimization.
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.
authors: Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd., 1-16-13, Kitakasai, Edogawa, Tokyo, 134-8630, Japan. nakaygoi@daiichipharm.co.jp
authors: Kiyoshi
authors: K
authors: Nakayama
authors: Yohei
authors: Y
authors: Ishida
authors: Masami
authors: M
authors: Ohtsuka
authors: Haruko
authors: H
authors: Kawato
authors: Ken ichi
authors: Ki
authors: Yoshida
authors: Yoshihiro
authors: Y
authors: Yokomizo
authors: Shigeru
authors: S
authors: Hosono
authors: Toshiharu
authors: T
authors: Ohta
authors: Kazuki
authors: K
authors: Hoshino
authors: Hiroko
authors: H
authors: Ishida
authors: Kumi
authors: K
authors: Yoshida
authors: Thomas E
authors: TE
authors: Renau
authors: Roger
authors: R
authors: Léger
authors: Jason Z
authors: JZ
authors: Zhang
authors: Ving J
authors: VJ
authors: Lee
authors: William J
authors: WJ
authors: Watkins
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism*; D001693:Biological Transport, Active / Q000187:drug effects*; D002352:Carrier Proteins / Q000378:metabolism*; D004352:Drug Resistance, Microbial; D015964:Gene Expression Regulation, Bacterial; D007769:Lactams / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000188:drug therapy; D011485:Protein Binding; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000378:metabolism*; D018805:Sepsis / Q000188:drug therapy; D012709:Serum Albumin / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D007769:Lactams; D026901:Membrane Transport Proteins; C118598:MexA protein, Pseudomonas aeruginosa; C118597:MexB protein, Pseudomonas aeruginosa; C402263:OprM protein, Pseudomonas aeruginosa; D012709:Serum Albumin