IQG-607 is a metal complex previously reported as a promising anti-tuberculosis (TB) drug against isoniazid (INH)-resistant strains of Unexpectedly, we found that INH-resistant clinical isolates were resistant to IQG-607. Spontaneous mutants resistant to IQG-607 were subjected to whole-genome sequencing, and all sequenced colonies carried alterations in the gene. The (S315T) mutation was sufficient to confer resistance to IQG-607 in both MIC assays and inside macrophages. Moreover, overexpression of the InhA(S94A) protein caused IQG-607's resistance.
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http://dx.doi.org/10.1128/AAC.02222-17 | DOI Listing |
Dalton Trans
November 2020
Group of Bioinorganic, Department of Organic and Inorganic Chemistry, Federal University of Ceará, Fortaleza, Brazil.
Medicinal inorganic chemists have provided many strategies to tackle a myriad of diseases, pushing forward the frontiers of pharmacology. As an example, the fight against tuberculosis (TB), an infectious bacterial disease, has led to the development of metal-based compounds as potential drugs. This disease remains a current health issue causing over 1.
View Article and Find Full Text PDFFront Microbiol
May 2018
Centro de Pesquisas em Biologia Molecular e Funcional, Instituto Nacional de Ciência e Tecnologia em Tuberculose, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil.
The emergence of strains of resistant to isoniazid (INH) has underscored the need for the development of new anti-tuberculosis agents. INH is activated by the mycobacterial -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--enoyl-ACP(CoA) reductase (InhA), which plays a role in mycolic acid biosynthesis.
View Article and Find Full Text PDFJ Inorg Biochem
February 2018
CNRS, LCC (Laboratoire de Chimie de Coordination), 205, route de Narbonne, BP 44099, F-31077 Toulouse, Cedex 4, France; Université de Toulouse, UPS, INPT, F-31077 Toulouse, Cedex 4, France. Electronic address:
The emergence of multidrug-resistant strains of Mycobacterium tuberculosis (MTB) represents a major threat to global health. Isoniazid (INH) is a prodrug used in the first-line treatment of tuberculosis. It undergoes oxidation by a catalase-peroxidase KatG, leading to generation of an isonicotinoyl radical that reacts with NAD(H) forming the INH-NADH adduct as the active metabolite.
View Article and Find Full Text PDFAntimicrob Agents Chemother
February 2018
Instituto Nacional de Ciência e Tecnologia em Tuberculose (INCT-TB), Centro de Pesquisas em Biologia Molecular e Funcional, Instituto de Pesquisas Biomédicas, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, Brazil
IQG-607 is a metal complex previously reported as a promising anti-tuberculosis (TB) drug against isoniazid (INH)-resistant strains of Unexpectedly, we found that INH-resistant clinical isolates were resistant to IQG-607. Spontaneous mutants resistant to IQG-607 were subjected to whole-genome sequencing, and all sequenced colonies carried alterations in the gene. The (S315T) mutation was sufficient to confer resistance to IQG-607 in both MIC assays and inside macrophages.
View Article and Find Full Text PDFJ Inorg Biochem
November 2014
Department of Chemistry, University of Warwick, Coventry CV4 7AL, United Kingdom. Electronic address:
Tuberculosis has re-emerged as a worldwide threat, which has motivated the development of new drugs. The antituberculosis complex Na3[Fe(CN)5(isoniazid)] (IQG607) in particular is of interest on account of its ability to overcome resistance. IQG607 has the potential for redox-mediated-activation, in which an acylpyridine (isonicotinoyl) radical could be generated without assistance from the mycobacterial KatG enzyme.
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