MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 2: achieving activity in vivo through the use of alternative scaffolds

• Published in: Bioorganic & medicinal chemistry letters 2003-12, Vol.13 (23), p.4205-4208
• Main Authors: Nakayama, Kiyoshi, Ishida, Yohei, Ohtsuka, Masami, Kawato, Haruko, Yoshida, Ken-ichi, Yokomizo, Yoshihiro, Ohta, Toshiharu, Hoshino, Kazuki, Otani, Tsuyoshi, Kurosaka, Yuichi, Yoshida, Kumi, Ishida, Hiroko, Lee, Ving J., Renau, Thomas E., Watkins, William J.
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacology; Bacterial Outer Membrane Proteins - metabolism; Biological Transport, Active - drug effects; Carrier Proteins - metabolism; Drug Resistance, Microbial; Fluoroquinolones - pharmacology; Gene Expression Regulation, Bacterial; Lactams - metabolism; Levofloxacin; Membrane Transport Proteins - metabolism; Mice; Microbial Sensitivity Tests; Neutropenia - drug therapy; Ofloxacin - pharmacology; Protein Binding; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - metabolism; Rats; Sepsis - drug therapy; Serum Albumin - metabolism; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2003.07.027

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. Graphic