MexAB-OprM-specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 1: discovery and early strategies for lead optimization.
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.
Nakayama
Kiyoshi
K
Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd., 1-16-13, Kitakasai, Edogawa, Tokyo, 134-8630, Japan. nakaygoi@daiichipharm.co.jp
Ishida
Yohei
Y
Ohtsuka
Masami
M
Kawato
Haruko
H
Yoshida
Ken ichi
Ki
Yokomizo
Yoshihiro
Y
Hosono
Shigeru
S
Ohta
Toshiharu
T
Hoshino
Kazuki
K
Ishida
Hiroko
H
Yoshida
Kumi
K
Renau
Thomas E
TE
Léger
Roger
R
Zhang
Jason Z
JZ
Lee
Ving J
VJ
Watkins
William J
WJ
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
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