Small Molecules Targeting Mycobacterium tuberculosis Type II NADH Dehydrogenase Exhibit Antimycobacterial Activity.

Autor: Harbut MB; California Institute for Biomedical Research, La Jolla, CA, 92037, USA., Yang B; California Institute for Biomedical Research, La Jolla, CA, 92037, USA., Liu R; California Institute for Biomedical Research, La Jolla, CA, 92037, USA., Yano T; Department of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Vilchèze C; Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA., Cheng B; California Institute for Biomedical Research, La Jolla, CA, 92037, USA., Lockner J; California Institute for Biomedical Research, La Jolla, CA, 92037, USA., Guo H; Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China., Yu C; California Institute for Biomedical Research, La Jolla, CA, 92037, USA., Franzblau SG; Institute for Tuberculosis Research, University of Illinois at Chicago, Chicago, IL, 60612, USA., Petrassi HM; California Institute for Biomedical Research, La Jolla, CA, 92037, USA., Jacobs WR Jr; Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA., Rubin H; Department of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Chatterjee AK; California Institute for Biomedical Research, La Jolla, CA, 92037, USA., Wang F; Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.; California Institute for Biomedical Research, La Jolla, CA, 92037, USA.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2018 Mar 19; Vol. 57 (13), pp. 3478-3482. Date of Electronic Publication: 2018 Feb 22.
DOI: 10.1002/anie.201800260
Abstrakt: The generation of ATP through oxidative phosphorylation is an essential metabolic function for Mycobaterium tuberculosis (Mtb), regardless of the growth environment. The type II NADH dehydrogenase (Ndh-2) is the conduit for electrons into the pathway, and is absent in the mammalian genome, thus making it a potential drug target. Herein, we report the identification of two types of small molecules as selective inhibitors for Ndh-2 through a multicomponent high-throughput screen. Both compounds block ATP synthesis, lead to effects consistent with loss of NADH turnover, and importantly, exert bactericidal activity against Mtb. Extensive medicinal chemistry optimization afforded the best analogue with an MIC of 90 nm against Mtb. Moreover, the two scaffolds have differential inhibitory activities against the two homologous Ndh-2 enzymes in Mtb, which will allow precise control over Ndh-2 function in Mtb to facilitate the assessment of this anti-TB drug target.
(© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
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