Addressing the stability of C-capped dipeptide efflux pump inhibitors that potentiate the activity of levofloxacin in Pseudomonas aeruginosa.
Synthetic optimization of a biologically labile class of dipeptides that function as efflux pump inhibitors to potentiate the antibacterial agent levofloxacin in Pseudomonas aeruginosa has led to the discovery of a related series of compounds that are completely stable in a variety of biological matrices. Other than the stability profile, the in vitro profile of the new series is essentially identical to that observed with the original one. A prototypical compound from the new series demonstrates potentiation in an in vivo model of infection.
Microcide Pharmaceuticals, Inc., Mountain View, CA 94043, USA. tomrenau@microcide.com
T E
TE
Renau
R
R
Léger
E M
EM
Flamme
M W
MW
She
C L
CL
Gannon
K M
KM
Mathias
O
O
Lomovskaya
S
S
Chamberland
V J
VJ
Lee
T
T
Ohta
K
K
Nakayama
Y
Y
Ishida
D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001693:Biological Transport, Active / Q000187:drug effects; D004151:Dipeptides / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004355:Drug Stability; D004357:Drug Synergism; D064704:Levofloxacin; D051379:Mice; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D015394:Molecular Structure; D015242:Ofloxacin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D013329:Structure-Activity Relationship
D000890:Anti-Infective Agents; D004151:Dipeptides; D064704:Levofloxacin; D015242:Ofloxacin