Is IQG-607 a Potential Metallodrug or Metallopro-Drug With a Defined Molecular Target in Mycobacterium tuberculosis ?

Frontiers in Microbiology
Bruno Lopes AbbadiLuiz Augusto Basso

Abstract

The emergence of strains of Mycobacterium tuberculosis resistant to isoniazid (INH) has underscored the need for the development of new anti-tuberculosis agents. INH is activated by the mycobacterial katG-encoded catalase-peroxidase, forming an acylpyridine fragment that is covalently attached to the C4 of NADH. This isonicotinyl-NAD adduct inhibits the activity of 2-trans-enoyl-ACP(CoA) reductase (InhA), which plays a role in mycolic acid biosynthesis. A metal-based INH analog, Na3[FeII(CN)5(INH)]·4H2O, IQG-607, was designed to have an electronic redistribution on INH moiety that would lead to an intramolecular electron transfer to bypass KatG activation. HPLC and EPR studies showed that the INH moiety can be oxidized by superoxide or peroxide yielding similar metabolites and isonicotinoyl radical only when associated to IQG-607, thereby supporting redox-mediated drug activation as a possible mechanism of action. However, IQG-607 was shown to inhibit the in vitro activity of both wild-type and INH-resistant mutant InhA enzymes in the absence of KatG activation. IQG-607 given by the oral route to M. tuberculosis-infected mice reduced lung lesions. Experiments using early and late controls of infection revealed a bactericidal ac...Continue Reading

References

Jun 1, 1980·The American Review of Respiratory Disease·A JindaniD A Mitchison
Nov 1, 1982·The Journal of Antimicrobial Chemotherapy·P MännistoU Lamminsivu
Oct 1, 1981·British Journal of Anaesthesia·W I BissetJ Reglinski
Oct 6, 1997·Proceedings of the National Academy of Sciences of the United States of America·V PelicicC Guilhot
Jun 5, 2002·Journal of Clinical Pharmacology·Marilyn N Martinez, Gordon L Amidon
Aug 8, 2002·Current Pharmaceutical Biotechnology·E K SchroederL A Basso
Mar 26, 2003·Antimicrobial Agents and Chemotherapy·Srinivas V RamaswamyEdward A Graviss
Aug 2, 2003·Current Opinion in Cell Biology·Michel Desjardins, Gareth Griffiths
Sep 6, 2003·Journal of Clinical Microbiology·Márcia Susana N SilvaMaria Lucia R Rossetti
Aug 13, 1960·British Medical Journal·D A EVANSV A McKUSICK
Nov 19, 2003·Proceedings of the National Academy of Sciences of the United States of America·Richa RawatPeter J Tonge
May 7, 2004·The Journal of Antimicrobial Chemotherapy·Rajesh Pandey, G K Khuller
Jan 13, 2005·British Journal of Pharmacology·Lee JiaMarina Protopopova
Jan 15, 2005·Microbial Drug Resistance : MDR : Mechanisms, Epidemiology, and Disease·L MoZ W Chen
Sep 22, 2005·Journal of the American Chemical Society·Reza A GhiladiPaul R Ortiz de Montellano
Aug 15, 2006·Nature Medicine·Catherine VilchèzeWilliam R Jacobs
Oct 6, 2006·American Journal of Respiratory and Critical Care Medicine·Jussi J SaukkonenUNKNOWN ATS (American Thoracic Society) Hepatotoxicity of Antituberculosis Therapy Subcommittee
Dec 25, 2007·Current Opinion in Chemical Biology·Pieter C A Bruijnincx, Peter J Sadler
Jan 29, 2008·Current Drug Metabolism·Paolo Preziosi
May 20, 2008·Tuberculosis
Feb 20, 2009·Chemical Communications : Chem Comm·Eric Meggers
Apr 25, 2009·Cellular Microbiology·Thomas Areschoug, Siamon Gordon
Jun 6, 2009·Pediatrics International : Official Journal of the Japan Pediatric Society·Yakup ErgulEthem Erginoz
Jul 7, 2009·The Journal of Antimicrobial Chemotherapy·Indra L BergvalRichard M Anthony
Jan 8, 2010·Protein Science : a Publication of the Protein Society·Christine E CadeReza A Ghiladi
May 4, 2010·Angewandte Chemie·Alexander WilbuerEric Meggers

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Citations

Jun 26, 2020·Dalton Transactions : an International Journal of Inorganic Chemistry·Luiz G F LopesEduardo H S Sousa
Jul 18, 2020·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Eduardo H S SousaJosé J G Moura
Jul 31, 2020·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Edinilton Muniz CarvalhoVania Bernardes-Génisson
Oct 15, 2020·International Journal of Pharmaceutics·Roselene KrothThiago Caon

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Methods Mentioned

BETA
NMR
acetylation

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