Abstract
New antitubercular agents are needed to combat the spread of multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis. The frontline antitubercular drug isoniazid (INH) targets the mycobacterial enoyl-ACP reductase, InhA. Resistance to INH is predominantly through mutations affecting the prodrug-activating enzyme KatG. Here, we report the identification of the diazaborines as a new class of direct InhA inhibitors. The lead compound, AN12855, exhibited in vitro bactericidal activity against replicating bacteria and was active against several drug-resistant clinical isolates. Biophysical and structural investigations revealed that AN12855 binds to and inhibits the substrate-binding site of InhA in a cofactor-independent manner. AN12855 showed good drug exposure after i.v. and oral delivery, with 53% oral bioavailability. Delivered orally, AN12855 exhibited dose-dependent efficacy in both an acute and chronic murine model of tuberculosis infection that was comparable with INH. Combined, AN12855 is a promising candidate for the development of new antitubercular agents.
Highlights
Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is a major public health threat
Unlike the INH–NAD adduct that competes with NADH binding to InhA GSK693, PT70 and NITD-916 block access to the InhA substratebinding site by occupying the fatty acyl substrate-binding pocket in a cofactor-dependent manner (Luckner et al, 2010; Hartkoorn et al, 2014; Manjunatha et al, 2015)
We describe the identification of a novel diazaborine scaffold that inhibits InhA in M. tuberculosis
Summary
Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is a major public health threat. Unlike the INH–NAD adduct that competes with NADH binding to InhA GSK693, PT70 and NITD-916 block access to the InhA substratebinding site by occupying the fatty acyl substrate-binding pocket in a cofactor-dependent manner (Luckner et al, 2010; Hartkoorn et al, 2014; Manjunatha et al, 2015). A promising observation from these studies is the lower frequency of resistance for direct inhibitors of InhA with 1 × 10−8 for NITD-916 and GSK625 compared with 1 × 10−5 for INH (Manjunatha et al, 2015; Martınez-Hoyos et al, 2016). Further studies are required to determine if differences in the in vitro frequency of resistance correlate with reduced resistance frequency in vivo
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