Identification of novel potent bicyclic peptide deformylase inhibitors.
Screening of our compound collection using Staphylococcus aureus Ni-Peptide deformylase (PDF) afforded a very potent PDF inhibitor with an IC(50) in the low nanomolar range but with poor antibacterial activity (MIC). Three-dimensional structural information obtained from Pseudomonas aeruginosa Ni-PDF complexed with the inhibitor suggested the synthesis of a variety of analogues that would maintain high binding affinity while attempting to improve antibacterial activity. Many of the compounds synthesized proved to be excellent PDF-Ni inhibitors and some showed increased antibacterial activity in selected strains.
Molteni
Valentina
V
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA. vmolteni@gnf.org
He
Xiaohui
X
Nabakka
Juliet
J
Yang
Kunyong
K
Kreusch
Andreas
A
Gordon
Perry
P
Bursulaya
Badry
B
Warner
Ian
I
Shin
Tanya
T
Biorac
Tanya
T
Ryder
Neil S
NS
Goldberg
Ron
R
Doughty
John
J
He
Yun
Y
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D008826:Microbial Sensitivity Tests; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology
D001643:Bridged Bicyclo Compounds; D011480:Protease Inhibitors; D000581:Amidohydrolases; C084507:peptide deformylase