Peptide deformylase inhibitors of Mycobacterium tuberculosis: synthesis, structural investigations, and biological results.
Bacterial peptide deformylase (PDF) belongs to a subfamily of metalloproteases catalyzing the removal of the N-terminal formyl group from newly synthesized proteins. We report the synthesis and biological activity of highly potent inhibitors of Mycobacterium tuberculosis (Mtb) PDF enzyme as well as the first X-ray crystal structure of Mtb PDF. Structure-activity relationship and crystallographic data clarified the structural requirements for high enzyme potency and cell based potency. Activities against single and multi-drug-resistant Mtb strains are also reported.
Pichota
Arkadius
A
Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore. arkadius.pichota@novartis.com
Duraiswamy
Jeyaraj
J
Yin
Zheng
Z
Keller
Thomas H
TH
Alam
Jenefer
J
Liung
Sarah
S
Lee
Gladys
G
Ding
Mei
M
Wang
Gang
G
Chan
Wai Ling
WL
Schreiber
Mark
M
Ma
Ida
I
Beer
David
D
Ngew
Xinyi
X
Mukherjee
Kakoli
K
Nanjundappa
Mahesh
M
Teo
Jeanette W P
JW
Thayalan
Pamela
P
Yap
Amelia
A
Dick
Thomas
T
Meng
Wuyi
W
Xu
Mei
M
Koehn
James
J
Pan
Shi-Hao
SH
Clark
Kirk
K
Xie
Xiaoling
X
Shoen
Carolyn
C
Cynamon
Michael
M
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000995:Antitubercular Agents / Q000737:chemistry / Q000627:therapeutic use*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D018432:Drug Resistance, Multiple; D024841:Fluoroquinolones / Q000494:pharmacology; D000077734:Gatifloxacin; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D008956:Models, Chemical; D008968:Molecular Conformation; D009163:Mycobacterium bovis / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D014376:Tuberculosis / Q000188:drug therapy*
D000995:Antitubercular Agents; D024841:Fluoroquinolones; D000581:Amidohydrolases; C084507:peptide deformylase; D000077734:Gatifloxacin