Whole Cell Active Inhibitors of Mycobacterial Lipoamide Dehydrogenase Afford Selectivity over the Human Enzyme through Tight Binding Interactions.

ACS infectious diseases, Volume: 7, Issue: 2
February 12, 2021
John Ginn J, Xiuju Jiang X, Shan Sun S, Mayako Michino M, David J Huggins DJ, Zodwa Mbambo Z, Robert Jansen R, Kyu Y Rhee KY, Nancy Arango N, Christopher D Lima CD, Nigel Liverton N, Toshihiro Imaeda T, Rei Okamoto R, Takanobu Kuroita T, Kazuyoshi Aso K, Andrew Stamford A, Michael Foley M, Peter T Meinke PT, Carl Nathan C, Ruslana Bryk R

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 but lacked activity against whole mycobacteria. Here we present the development of analogs with improved permeability, potency, and selectivity, which inhibit the growth of 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.

Courtesy of the U.S. National Library of Medicine