The isoniazid-NAD adduct is a slow, tight-binding inhibitor of InhA, the Mycobacterium tuberculosis enoyl reductase: adduct affinity and drug resistance

Proceedings of the National Academy of Sciences of the United States of America
Richa RawatPeter J Tonge

Abstract

Isoniazid (INH), a frontline antitubercular drug, inhibits InhA, the enoyl reductase from Mycobacterium tuberculosis, by forming a covalent adduct with the NAD cofactor. Here, we report that the INH-NAD adduct is a slow, tight-binding competitive inhibitor of InhA. Demonstration that the adduct binds to WT InhA by a two-step enzyme inhibition mechanism, with initial, weak binding (K(-1) = 16 +/- 11 nM) followed by slow conversion to a final inhibited complex (EI*) with overall Ki = 0.75 +/- 0.08 nM, reconciles existing contradictory values for the inhibitory potency of INH-NAD for InhA. The first order rate constant for conversion of the initial EI complex to EI* (k2 = 0.13 +/- 0.01 min(-1)) is similar to the maximum rate constant observed for InhA inhibition in reaction mixtures containing InhA, INH, NADH, and the INH-activating enzyme KatG (catalase/peroxidase from M. tuberculosis), consistent with an inhibition mechanism in which the adduct forms in solution rather than on the enzyme. Importantly, three mutations that correlate with INH resistance, I21V, I47T, and S94A, have little impact on the inhibition constants. Thus, drug resistance does not result simply from a reduction in affinity of INH-NAD for pure InhA. Instead, ...Continue Reading

References

Aug 21, 1992·Science·B R Bloom, C J Murray
Oct 1, 1995·Clinical Microbiology Reviews·J M Musser
Jun 11, 1998·Emerging Infectious Diseases·A RattanN Ahmad
Aug 26, 1998·Nature·L M McMurryS B Levy
Jun 26, 1999·The Journal of Antimicrobial Chemotherapy·C M BébéarC Bébéar
Oct 3, 1999·Angewandte Chemie·M Wilming, K Johnsson
Oct 27, 1999·Proceedings of the National Academy of Sciences of the United States of America·M WilsonG K Schoolnik
Mar 26, 2003·Antimicrobial Agents and Chemotherapy·Srinivas V RamaswamyEdward A Graviss
Mar 26, 2003·The Journal of Biological Chemistry·Laurent KremerGurdyal S Besra

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Citations

Dec 2, 2011·Systems and Synthetic Biology·Ashwini G BhatNagasuma Chandra
Jan 16, 2008·Accounts of Chemical Research·Hao Lu, Peter J Tonge
Nov 23, 2006·Biochemistry·Argyrides ArgyrouJohn S Blanchard
Oct 25, 2011·Biochemistry·Janine G BorgaroPeter J Tonge
Apr 23, 2013·Journal of Chemical Information and Modeling·Tomohiro KinjoShunsuke Aoki
May 2, 2006·Nature Structural & Molecular Biology·Argyrides ArgyrouJohn S Blanchard
Dec 19, 2009·The Journal of Biological Chemistry·Carl A MachuttaPeter J Tonge
Jun 18, 2010·The Journal of Biological Chemistry·Ben WisemanPeter C Loewen
Aug 16, 2008·The Journal of Biological Chemistry·Nicole A KruhPeter J Tonge
Jul 19, 2012·Journal of Biomolecular Structure & Dynamics·Jyothi PadiadpuNagasuma Chandra
Jan 18, 2007·Microbial Drug Resistance : MDR : Mechanisms, Epidemiology, and Disease·Xin JiangHonghai Wang
Apr 21, 2005·Bioinformatics·Lawrence CabusoraChristian V Forst
Sep 8, 2009·The Journal of Antimicrobial Chemotherapy·Kathleen EnglandRichard A Slayden
Mar 12, 2011·The Journal of Antimicrobial Chemotherapy·Nina LiuPeter J Tonge
May 12, 2011·The Journal of Antimicrobial Chemotherapy·Pedro Eduardo Almeida Almeida Da Silva, Juan Carlos Palomino
Dec 12, 2012·The Journal of Antimicrobial Chemotherapy·Ashley J WarmanGiancarlo A Biagini
Apr 18, 2007·Antimicrobial Agents and Chemotherapy·Salman SiddiqiYing Zhang
Jul 28, 2006·Antimicrobial Agents and Chemotherapy·Manzour Hernando HazbónDavid Alland
Jun 2, 2011·Antimicrobial Agents and Chemotherapy·Catherine VilchèzeWilliam R Jacobs
Jun 23, 2010·Antimicrobial Agents and Chemotherapy·Feng WangJames C Sacchettini
Jan 28, 2005·Antimicrobial Agents and Chemotherapy·Catherine VilchèzeWilliam R Jacobs
Jun 15, 2005·Annual Review of Biochemistry·Stephen W White Rock
Nov 24, 2007·Annual Review of Microbiology·Catherine Vilchèze, William R Jacobs
Apr 12, 2005·Annual Review of Pharmacology and Toxicology·B Kevin ParkDominic P Williams
Sep 3, 2011·Future Medicinal Chemistry·Robert A Copeland
Sep 19, 2012·EMBO Molecular Medicine·Gerard D Wright
Sep 19, 2012·EMBO Molecular Medicine·Ruben C HartkoornStewart T Cole
Sep 29, 2011·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Eduardo Henrique Silva SousaIcaro de Sousa Moreira
Jun 2, 2012·Expert Opinion on Drug Discovery·Christopher H Miller, Ronan F O'Toole
Nov 11, 2014·Journal of Enzyme Inhibition and Medicinal Chemistry·Ondrej HolasMartin Dolezal
Nov 5, 2013·Journal of Microbiology, Immunology, and Infection = Wei Mian Yu Gan Ran Za Zhi·Shu-Ting TsengZhi-Yuan Shi

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