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

ACS Infect Dis. 2024 May 10;10(5):1561-1575. doi: 10.1021/acsinfecdis.3c00592. Epub 2024 Apr 5.

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.

Keywords: DEL; DNA encoded chemical library; TB drug discovery; inhibitor; polyketide synthase 13; thioesterase.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antitubercular Agents* / chemistry
  • Antitubercular Agents* / pharmacology
  • Antitubercular Agents* / therapeutic use
  • Bacterial Proteins / antagonists & inhibitors
  • Bacterial Proteins / chemistry
  • Crystallography, X-Ray
  • Disease Models, Animal
  • Drug Discovery
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors* / chemistry
  • Enzyme Inhibitors* / pharmacology
  • Humans
  • Mice
  • Mycobacterium tuberculosis* / drug effects
  • Mycobacterium tuberculosis* / enzymology
  • Polyketide Synthases* / chemistry
  • Polyketide Synthases* / genetics
  • Polyketide Synthases* / metabolism
  • Small Molecule Libraries* / chemistry
  • Small Molecule Libraries* / pharmacology
  • Thiolester Hydrolases* / antagonists & inhibitors
  • Thiolester Hydrolases* / chemistry
  • Thiolester Hydrolases* / genetics
  • Thiolester Hydrolases* / metabolism
  • Tuberculosis / drug therapy
  • Tuberculosis / microbiology

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • Enzyme Inhibitors
  • polyketide synthase Pks13, Mycobacterium tuberculosis
  • Polyketide Synthases
  • Small Molecule Libraries
  • Thiolester Hydrolases