Affiliation:
1. Department of Microbiology and Molecular Genetics, Michigan State University , East Lansing, Michigan, USA
Abstract
ABSTRACT
Nitro-containing compounds have emerged as important agents in the control of tuberculosis (TB). From a whole-cell high-throughput screen for
Mycobacterium tuberculosis
(Mtb) growth inhibitors, 10 nitro-containing compounds were prioritized for characterization and mechanism of action studies. HC2209, HC2210, and HC2211 are nitrofuran-based prodrugs that need the cofactor F
420
machinery for activation. Unlike pretomanid which depends only on deazaflavin-dependent nitroreductase (Ddn), these nitrofurans depend on Ddn and possibly another F
420
-dependent reductase for activation. These nitrofurans also differ from pretomanid in their potent activity against
Mycobacterium abscessus
. Four dinitrobenzamides (HC2217, HC2226, HC2238, and HC2239) and a nitrofuran (HC2250) are proposed to be inhibitors of decaprenyl-phosphoryl-ribose 2′-epimerase 1 (DprE1), based on isolation of resistant mutations in
dprE1
. Unlike other DprE1 inhibitors, HC2250 was found to be potent against non-replicating persistent bacteria, suggesting additional targets. Two of the compounds, HC2233 and HC2234, were found to have potent, sterilizing activity against replicating and non-replicating Mtb
in vitro
, but a proposed mechanism of action could not be defined. In a pilot
in vivo
efficacy study, HC2210 was orally bioavailable and efficacious in reducing bacterial load by ~1 log in a chronic murine TB infection model.
Funder
HHS | National Institutes of Health
AgBioResearch, Michigan State University
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology