Conformationally-restricted analogues of efflux pump inhibitors that potentiate the activity of levofloxacin in Pseudomonas aeruginosa.
Conformational restriction of the ornithine residue of the efflux pump inhibitor D-ornithine-D-homophenylalanine-3-aminoquinoline (MC-02,595, 2) furnished bioisosteric proline derivatives that were less toxic in vivo and as active as the lead in potentiating the activity of the fluoroquinolone levofloxacin via the inhibition of efflux pumps in Pseudomonas aeruginosa.
Renau
Thomas E
TE
Essential Therapeutics, Inc, 850Maude Avenue, Mountain View, CA 94043, USA. thomas.renau@roche.com
Léger
Roger
R
Filonova
Lubov
L
Flamme
Eric M
EM
Wang
Michael
M
Yen
Rose
R
Madsen
Deidre
D
Griffith
David
D
Chamberland
Suzanne
S
Dudley
Michael N
MN
Lee
Ving J
VJ
Lomovskaya
Olga
O
Watkins
William J
WJ
Ohta
Toshiharu
T
Nakayama
Kiyoshi
K
Ishida
Yohei
Y
D000613:Aminobutyrates / Q000737:chemistry; D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D001425:Bacterial Outer Membrane Proteins / Q000037:antagonists & inhibitors*; D004357:Drug Synergism; D007928:Lethal Dose 50; D064704:Levofloxacin; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D015242:Ofloxacin / Q000494:pharmacology*; D009952:Ornithine / Q000737:chemistry; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013329:Structure-Activity Relationship
D000613:Aminobutyrates; D000634:Aminoquinolines; D000890:Anti-Infective Agents; D001425:Bacterial Outer Membrane Proteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D064704:Levofloxacin; C014328:2-amino-4-phenylbutyric acid; D015242:Ofloxacin; D009952:Ornithine