MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 2: achieving activity in vivo through the use of alternative scaffolds.
Problems of low solubility, high serum protein binding, and lack of efficacy in vivo in first generation MexAB-OprM specific efflux pump inhibitors were addressed. Through the use of pharmacophore modelling, the key structural elements for pump inhibition were defined. Use of alternative scaffolds upon which the key elements were arrayed gave second generation leads with greatly improved physical properties and activity in the potentiation of antibacterial quinolones (levofloxacin and sitafloxacin) versus Pseudomonas aeruginosa in vivo.
Nakayama
Kiyoshi
K
Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd., 1-16-13, Kitakasai, Edogawa, Tokyo 134-8630, Japan. nakagoi@daiichipharm.co.jp
Ishida
Yohei
Y
Ohtsuka
Masami
M
Kawato
Haruko
H
Yoshida
Ken-ichi
K
Yokomizo
Yoshihiro
Y
Ohta
Toshiharu
T
Hoshino
Kazuki
K
Otani
Tsuyoshi
T
Kurosaka
Yuichi
Y
Yoshida
Kumi
K
Ishida
Hiroko
H
Lee
Ving J
VJ
Renau
Thomas E
TE
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; D024841:Fluoroquinolones / Q000494:pharmacology; D015964:Gene Expression Regulation, Bacterial; D007769:Lactams / Q000378:metabolism; D064704:Levofloxacin; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000188:drug therapy; D015242:Ofloxacin / Q000494:pharmacology; D011485:Protein Binding; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; 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; D024841:Fluoroquinolones; D007769:Lactams; D026901:Membrane Transport Proteins; C118598:MexA protein, Pseudomonas aeruginosa; C118597:MexB protein, Pseudomonas aeruginosa; C402263:OprM protein, Pseudomonas aeruginosa; D012709:Serum Albumin; D064704:Levofloxacin; C076246:sitafloxacin; D015242:Ofloxacin