Mycobacterium tuberculosis dihydrofolate reductase is a target for isoniazid

Nature Structural & Molecular Biology
Argyrides ArgyrouJohn S Blanchard

Abstract

Isoniazid is a key drug used in the treatment of tuberculosis. Isoniazid is a pro-drug, which, after activation by the katG-encoded catalase peroxidase, reacts nonenzymatically with NAD(+) and NADP(+) to generate several isonicotinoyl adducts of these pyridine nucleotides. One of these, the acyclic 4S isomer of isoniazid-NAD, targets the inhA-encoded enoyl-ACP reductase, an enzyme essential for mycolic acid biosynthesis in Mycobacterium tuberculosis. Here we show that the acyclic 4R isomer of isoniazid-NADP inhibits the M. tuberculosis dihydrofolate reductase (DHFR), an enzyme essential for nucleic acid synthesis. This biologically relevant form of the isoniazid adduct is a subnanomolar bisubstrate inhibitor of M. tuberculosis DHFR. Expression of M. tuberculosis DHFR in Mycobacterium smegmatis mc(2)155 protects cells against growth inhibition by isoniazid by sequestering the drug. Thus, M. tuberculosis DHFR is the first new target for isoniazid identified in the last decade.

References

Aug 21, 1992·Science·B R Bloom, C J Murray
May 14, 1998·Chemistry & Biology·G P Miller, S J Benkovic
Nov 26, 1998·Progress in Lipid Research·C E BarryY Yuan
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
Apr 12, 2002·Chembiochem : a European Journal of Chemical Biology·M NguyenB Meunier
May 18, 1963·Nature·S B FORMALR LAUNDY
Nov 19, 2003·Proceedings of the National Academy of Sciences of the United States of America·Richa RawatPeter J Tonge
Dec 25, 2003·Antimicrobial Agents and Chemotherapy·Stéphanie Ducasse-CabanotAnnaïk Quémard
May 14, 2004·Annual Review of Biophysics and Biomolecular Structure·Jason R SchnellPeter E Wright
Sep 1, 1994·Acta Crystallographica. Section D, Biological Crystallography·UNKNOWN Collaborative Computational Project, Number 4
Jan 18, 2005·Clinical Microbiology Reviews·Kuni TakayamaGurdyal S Besra
Jun 15, 2005·Annual Review of Biochemistry·Stephen W White Rock
Sep 2, 2005·Proceedings of the National Academy of Sciences of the United States of America·Palangpon KongsaereeYongyuth Yuthavong
Jan 7, 2006·Journal of Proteome Research·Minerva A HughesCraig A Townsend

❮ Previous
Next ❯

Citations

Jan 16, 2008·Accounts of Chemical Research·Hao Lu, Peter J Tonge
Nov 23, 2006·Biochemistry·Argyrides ArgyrouJohn S Blanchard
Dec 9, 2010·Biochemistry·Clarissa M CzeksterJohn S Blanchard
Jun 15, 2011·Journal of Chemical Information and Modeling·Kalidas Yeturu, Nagasuma Chandra
Aug 15, 2006·Nature Medicine·Catherine VilchèzeWilliam R Jacobs
Dec 15, 2007·Nature Reviews. Microbiology·James C SacchettiniJoel S Freundlich
Mar 4, 2011·Proceedings of the National Academy of Sciences of the United States of America·Jun-Rong WeiEric J Rubin
Oct 19, 2012·The Journal of Antimicrobial Chemotherapy·Juan Carlos Palomino, Anandi Martin
Jun 23, 2010·Antimicrobial Agents and Chemotherapy·Feng WangJames C Sacchettini
Jul 1, 2009·Antimicrobial Agents and Chemotherapy·Pierre ForgacsGlenn D Roberts
Jul 6, 2012·Clinical Microbiology Reviews·Barbara A Brown-ElliottRichard J Wallace
Nov 24, 2007·Annual Review of Microbiology·Catherine Vilchèze, William R Jacobs
Dec 19, 2008·BMC Bioinformatics·Kalidas Yeturu, Nagasuma Chandra
Jun 6, 2009·Future Microbiology·Giovanna RiccardiSilvia Buroni
Jun 18, 2014·European Journal of Medicinal Chemistry·N C DesaiPriyanka Desai
Aug 16, 2011·Biochimica Et Biophysica Acta·N M GoodeyK C Bagley
Oct 31, 2012·Expert Review of Anti-infective Therapy·Kerstin A Wolff, Liem Nguyen
Sep 25, 2010·Chemico-biological Interactions·Clinton R Nishida, Paul R Ortiz de Montellano
Sep 14, 2016·ACS Infectious Diseases·Mark P PereiraShana O Kelley
Nov 26, 2008·Chemico-biological Interactions·Rob Meijers, Eila Cedergren-Zeppezauer
Jun 24, 2008·International Journal of Antimicrobial Agents·Pedro E Almeida da SilvaMarcos A P Martins
Nov 1, 2006·Molecular Microbiology·Graham S Timmins, Vojo Deretic
Feb 24, 2011·Tropical Medicine & International Health : TM & IH·Alimuddin ZumlaJohn Grange
Apr 14, 2016·Future Microbiology·Juan Carlos Palomino, Anandi Martin
Aug 1, 2014·Current Opinion in Microbiology·Pooja Gopal, Thomas Dick
Mar 2, 2010·Journal of Molecular Biology·Judith ScobleTravis Beddoe
Nov 16, 2016·Journal of Biomolecular Structure & Dynamics·Parthiban MarimuthuVigneshwaran Namasivayam

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antitubercular Agents

Antitubercular agents are pharmacologic agents for treatment of tuberculosis. Discover the latest research on antitubercular agents here.

Antitubercular Agents (ASM)

Antitubercular agents are pharmacologic agents for treatment of tuberculosis. Discover the latest research on antitubercular agents here.