Whole cell active inhibitors of mycobacterial lipoamide dehydrogenase afford selectivity over the human enzyme through tight binding interactions Journal Article

   


Authors: Ginn, J.; Jiang, X.; Sun, S.; Michino, M.; Huggins, D. J.; Mbambo, Z.; Jansen, R.; Rhee, K. Y.; Arango, N.; Lima, C. D.; Liverton, N.; Imaeda, T.; Okamoto, R.; Kuroita, T.; Aso, K.; Stamford, A.; Foley, M.; Meinke, P. T.; Nathan, C.; Bryk, R.
Article Title: Whole cell active inhibitors of mycobacterial lipoamide dehydrogenase afford selectivity over the human enzyme through tight binding interactions
Abstract: Tuberculosis remains a leading cause of death from a single bacterial infection worldwide. Efforts to develop new treatment options call for expansion into an unexplored target space to expand the drug pipeline and bypass resistance to current antibiotics. Lipoamide dehydrogenase is a metabolic and antioxidant enzyme critical for mycobacterial growth and survival in mice. Sulfonamide analogs were previously identified as potent and selective inhibitors of mycobacterial lipoamide dehydrogenase in vitro but lacked activity against whole mycobacteria. Here we present the development of analogs with improved permeability, potency, and selectivity, which inhibit the growth of Mycobacterium tuberculosis in axenic culture on carbohydrates and within mouse primary macrophages. They increase intrabacterial pyruvate levels, supporting their on-target activity within mycobacteria. Distinct modalities of binding between the mycobacterial and human enzymes contribute to improved potency and hence selectivity through induced-fit tight binding interactions within the mycobacterial but not human enzyme, as indicated by kinetic analysis and crystallography. © 2021 American Chemical Society.
Keywords: controlled study; drug penetration; nonhuman; animal cell; mouse; animal experiment; animal model; drug potency; in vitro study; inhibitor; drug selectivity; structure activity relation; mycobacterium tuberculosis; sulfonamide; hydrogen bond; macrophage; tuberculosis; growth inhibition; crystallography; drug solubility; pyruvate dehydrogenase; pyruvic acid; antibacterial activity; lipoamide dehydrogenase; dihydrolipoamide dehydrogenase; minimum inhibitory concentration; mycobacteria; nitrosative stress; whole cell; priority journal; article; oxidoreductase inhibitor; metabolic clearance; ic50; metabolic stability; association rate constant; maximum concentration; residence time; slow binding; tight binding; axenic culture
Journal Title: ACS Infectious Diseases
Volume: 7
Issue: 2
ISSN: 2373-8227
Publisher: American Chemical Society  
Date Published: 2021-02-12
Start Page: 435
End Page: 444
Language: English
DOI: 10.1021/acsinfecdis.0c00788
PUBMED: 33527832
PROVIDER: scopus
PMCID: PMC7888283
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85102098533&doi=10.1021%2facsinfecdis.0c00788&partnerID=40&md5=190108ce39553f5dd8e3fdf4022e7503
Notes: Article -- Export Date: 1 April 2021 -- Source: Scopus
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MSK Authors
  1. Christopher D Lima
    103 Lima
  2. Nancy M Arango
    7 Arango
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