Inhibitors of the Thioesterase Activity of Mycobacterium tuberculosis Pks13 Discovered Using DNA-Encoded Chemical Library Screening.

TitleInhibitors of the Thioesterase Activity of Mycobacterium tuberculosis Pks13 Discovered Using DNA-Encoded Chemical Library Screening.
Publication TypeJournal Article
Year of Publication2024
AuthorsKrieger IV, Yalamanchili S, Dickson P, Engelhart CA, Zimmerman MD, Wood J, Clary E, Nguyen J, Thornton N, Centrella PA, Chan B, Cuozzo JW, Gengenbacher M, GuiƩ M-A, Guilinger JP, Bienstock C, Hartl H, Hupp CD, Jetson R, Satoh T, Yeoman JTS, Zhang Y, Dartois V, Schnappinger D, Keefe AD, Sacchettini JC
JournalACS Infect Dis
Volume10
Issue5
Pagination1561-1575
Date Published2024 May 10
ISSN2373-8227
KeywordsAnimals, Antitubercular Agents, Bacterial Proteins, Crystallography, X-Ray, Disease Models, Animal, Drug Discovery, Drug Evaluation, Preclinical, Enzyme Inhibitors, Humans, Mice, Mycobacterium tuberculosis, Polyketide Synthases, Small Molecule Libraries, Thiolester Hydrolases, Tuberculosis
Abstract

DNA-encoded chemical library (DEL) technology provides a time- and cost-efficient method to simultaneously screen billions of compounds for their affinity to a protein target of interest. Here we report its use to identify a novel chemical series of inhibitors of the thioesterase activity of polyketide synthase 13 (Pks13) from Mycobacterium tuberculosis (Mtb). We present three chemically distinct series of inhibitors along with their enzymatic and Mtb whole cell potency, the measure of on-target activity in cells, and the crystal structures of inhibitor-enzyme complexes illuminating their interactions with the active site of the enzyme. One of these inhibitors showed a favorable pharmacokinetic profile and demonstrated efficacy in an acute mouse model of tuberculosis (TB) infection. These findings and assay developments will aid in the advancement of TB drug discovery.

DOI10.1021/acsinfecdis.3c00592
Alternate JournalACS Infect Dis
PubMed ID38577994
PubMed Central IDPMC11091879
Grant ListP01 AI095208 / AI / NIAID NIH HHS / United States

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