Inhibitors of the Thioesterase Activity of Mycobacterium tuberculosis Pks13 Discovered Using DNA-Encoded Chemical Library Screening.
Inna V KriegerSubbarao YalamanchiliPaige DicksonCurtis A EngelhartMatthew D ZimmermanJeremy WoodEthan ClaryJasmine NguyenNatalie ThorntonPaolo A CentrellaBetty ChanJohn W CuozzoMartin GengenbacherMarie-Aude GuiéJohn P GuilingerCorey BienstockHajnalka HartlChristopher D HuppRachael JetsonTakashi SatohJohn T S YeomanYing ZhangVeronique Anne DartoisDirk SchnappingerAnthony D KeefeJames C SacchettiniPublished in: ACS infectious diseases (2024)
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.
Keyphrases
- mycobacterium tuberculosis
- pulmonary tuberculosis
- drug discovery
- mouse model
- high throughput
- circulating tumor
- induced apoptosis
- liver failure
- single cell
- cell free
- emergency department
- hydrogen peroxide
- cell therapy
- intensive care unit
- cell death
- nitric oxide
- hepatitis c virus
- binding protein
- mass spectrometry
- amino acid
- nucleic acid
- protein protein
- endoplasmic reticulum stress
- aortic dissection