N-alkyl urea hydroxamic acids as a new class of peptide deformylase inhibitors with antibacterial activity.
Peptide deformylase (PDF) is a prokaryotic metalloenzyme that is essential for bacterial growth and is a new target for the development of antibacterial agents. All previously reported PDF inhibitors with sufficient antibacterial activity share the structural feature of a 2-substituted alkanoyl at the P(1)' site. Using a combination of iterative parallel synthesis and traditional medicinal chemistry, we have identified a new class of PDF inhibitors with N-alkyl urea at the P(1)' site. Compounds with MICs of <or=4 micro g/ml against gram-positive and gram-negative pathogens, including Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae, have been identified. The concentrations needed to inhibit 50% of enzyme activity (IC(50)s) for Escherichia coli Ni-PDF were <or=0.1 micro M, demonstrating the specificity of the inhibitors. In addition, these compounds were very selective for PDF, with IC(50)s of consistently >200 micro M for matrilysin and other mammalian metalloproteases. Structure-activity relationship analysis identified preferred substitutions resulting in improved potency and decreased cytotoxity. One of the compounds (VRC4307) was cocrystallized with PDF, and the enzyme-inhibitor structure was determined at a resolution of 1.7 A. This structural information indicated that the urea compounds adopt a binding position similar to that previously determined for succinate hydroxamates. Two compounds, VRC4232 and VRC4307, displayed in vivo efficacy in a mouse protection assay, with 50% protective doses of 30.8 and 17.9 mg/kg of body weight, respectively. These N-alkyl urea hydroxamic acids provide a starting point for identifying new PDF inhibitors that can serve as antimicrobial agents.
Versicor, Inc., Fremont, California 94555, USA.
Corinne J
CJ
Hackbarth
Dawn Z
DZ
Chen
Jason G
JG
Lewis
Kirk
K
Clark
James B
JB
Mangold
Jeffrey A
JA
Cramer
Peter S
PS
Margolis
Wen
W
Wang
Jim
J
Koehn
Charlotte
C
Wu
S
S
Lopez
George
G
Withers
Helen
H
Gu
Elina
E
Dunn
R
R
Kulathila
Shi-Hao
SH
Pan
Wilma L
WL
Porter
Jeff
J
Jacobs
Joaquim
J
Trias
Dinesh V
DV
Patel
Beat
B
Weidmann
Richard J
RJ
White
Zhengyu
Z
Yuan
D000581:Amidohydrolases; D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000818:Animals; D001419:Bacteria / Q000187:drug effects; D001711:Biotransformation; D018360:Crystallography, X-Ray; D017931:DNA Primers; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D004926:Escherichia coli / Q000378:metabolism; D005260:Female; D006193:Haemophilus influenzae / Q000187:drug effects / Q000235:genetics; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000378:metabolism; D008968:Molecular Conformation; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000188:drug therapy / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000235:genetics; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology
D017931:DNA Primers; D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D014508:Urea; D000626:Aminopeptidases; D000581:Amidohydrolases; C084507:peptide deformylase