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Abstract
We report GSK3011724A (DG167) as a binary inhibitor of β-ketoacyl-ACP synthase (KasA) in Mycobacterium tuberculosis Genetic and biochemical studies established KasA as the primary target. The X-ray crystal structure of the KasA-DG167 complex refined to 2.0-Å resolution revealed two interacting DG167 molecules occupying nonidentical sites in the substrate-binding channel of KasA. The binding affinities of KasA to DG167 and its analog, 5g, which binds only once in the substrate-binding channel, were determined, along with the KasA-5g X-ray crystal structure. DG167 strongly augmented the in vitro activity of isoniazid (INH), leading to synergistic lethality, and also synergized in an acute mouse model of M. tuberculosis infection. Synergistic lethality correlated with a unique transcriptional signature, including upregulation of oxidoreductases and downregulation of molecular chaperones. The lead structure-activity relationships (SAR), pharmacokinetic profile, and detailed interactions with the KasA protein that we describe may be applied to evolve a next-generation therapeutic strategy for tuberculosis (TB).IMPORTANCE Cell wall biosynthesis inhibitors have proven highly effective for treating tuberculosis (TB). We discovered and validated members of the indazole sulfonamide class of small molecules as inhibitors of Mycobacterium tuberculosis KasA-a key component for biosynthesis of the mycolic acid layer of the bacterium's cell wall and the same pathway as that inhibited by the first-line antitubercular drug isoniazid (INH). One lead compound, DG167, demonstrated synergistic lethality in combination with INH and a transcriptional pattern consistent with bactericidality and loss of persisters. Our results also detail a novel dual-binding mechanism for this compound as well as substantial structure-activity relationships (SAR) that may help in lead optimization activities. Together, these results suggest that KasA inhibition, specifically, that shown by the DG167 series, may be developed into a potent therapy that can synergize with existing antituberculars.
Highlights
We report GSK3011724A (DG167) as a binary inhibitor of -ketoacylACP synthase (KasA) in Mycobacterium tuberculosis
We screened a library of 168 compounds with established antitubercular whole-cell efficacy for putative cell wall inhibitors [8] using a previously described M. bovis BCG strain harboring a lacZ reporter fused to the M. tuberculosis iniBAC promoter (PiniBAC) [10,11,12]
Twenty-two of the unique dual-drug-modulated genes were downregulated (Table S2C). This set of downregulated genes was enriched for chaperones, which are typically upregulated after treatment with bacteriostatic drugs [40,41,42] and are upregulated in M. tuberculosis persisters during INH exposure. These results suggest that combined treatment with both DG167 and INH activates a cellular response associated with loss of persistence and induction of cidality that is distinct from the cellular response induced by single-drug treatment
Summary
We report GSK3011724A (DG167) as a binary inhibitor of -ketoacylACP synthase (KasA) in Mycobacterium tuberculosis. We discovered and validated members of the indazole sulfonamide class of small molecules as inhibitors of Mycobacterium tuberculosis KasA—a key component for biosynthesis of the mycolic acid layer of the bacterium’s cell wall and the same pathway as that inhibited by the first-line antitubercular drug isoniazid (INH). Our results detail a novel dual-binding mechanism for this compound as well as substantial structure-activity relationships (SAR) that may help in lead optimization activities Together, these results suggest that KasA inhibition, spe-. Renewed efforts to find new antitubercular leads have led to the discovery of thousands of whole-cell active compounds and novel chemotypes. Many of these compounds are undergoing optimization to deliver a lead for further drug development [7,8,9]. This screen led to the discovery of the thiophenes as inhibitors of polyketide synthase 13 (Pks13) [11] and of DA5/DA8 as inhibitors of MmpL3 [12]
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