Affiliation:
1. Translational Health Sciences and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India
2. Department of Life Science, Laboratory of Mycobacterial Immunology, National Institute of Technology, Rourkela, India
Abstract
ABSTRACT
New drugs with novel mechanisms of action are urgently needed to tackle the issue of drug-resistant tuberculosis. Here, we have performed phenotypic screening using the Pathogen Box library obtained from the Medicines for Malaria Venture against
Mycobacterium tuberculosis in vitro
. We have identified a pyridine carboxamide derivative, MMV687254, as a promising hit. This molecule is specifically active against
M. tuberculosis
and
Mycobacterium bovis
Bacillus Calmette-Guérin (
M. bovis
BCG) but inactive against
Enterococcus faecalis
,
Staphylococcus aureus
,
Klebsiella pneumoniae
,
Acinetobacter baumanii
,
Pseudomonas aeruginosa
, and
Escherichia coli
pathogens. We demonstrate that MMV687254 inhibits
M. tuberculosis
growth in liquid cultures in a bacteriostatic manner. Surprisingly, MMV687254 was as active as isoniazid in macrophages and inhibited
M. tuberculosis
growth in a bactericidal manner. Mechanistic studies revealed that MMV687254 is a prodrug and that its anti-mycobacterial activity requires AmiC
-
dependent hydrolysis. We further demonstrate that MMV687254 inhibits
M. tuberculosis
growth in macrophages by inducing autophagy. In the present study, we have also carried out a detailed structure-activity relationship study and identified a promising novel lead candidate. The identified novel series of compounds also showed activity against drug-resistant
M. bovis
BCG and
M. tuberculosis
clinical strains. Finally, we demonstrate that in contrast to MMV687254, the lead molecule was able to inhibit
M. tuberculosis
growth in a chronic mouse model of infection. Taken together, we have identified a novel lead molecule with a dual mechanism of action that can be further optimized to design more potent anti-tubercular agents.
Funder
Department of Biotechnology, Ministry of Science and Technology, India
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology