Revisiting Activation of and Mechanism of Resistance to Compound IQG-607 in Mycobacterium tuberculosis-Reference-Cited by-同舟云学术

Revisiting Activation of and Mechanism of Resistance to Compound IQG-607 in Mycobacterium tuberculosis

Published:2018-02 Issue:2 Volume:62 Page:
ISSN:0066-4804
Container-title:Antimicrobial Agents and Chemotherapy
language:en
Short-container-title:Antimicrob Agents Chemother

Author:

Abbadi Bruno L.¹²^ORCID,Villela Anne D.¹,Rodrigues-Junior Valnês S.¹,Subtil Fernanda T.¹²,Dalberto Pedro F.¹²,Pinheiro Ana P. S.¹²,Santos Diógenes S.¹³,Machado Pablo¹³,Basso Luiz A.¹²,Bizarro Cristiano V.¹²^ORCID

Affiliation:

1. 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

2. Faculdade de Biociências, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

3. Faculdade de Farmácia, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

Abstract

ABSTRACT IQG-607 is a metal complex previously reported as a promising anti-tuberculosis (TB) drug against isoniazid (INH)-resistant strains of Mycobacterium tuberculosis . 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 katG gene. The katG (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.

Funder

Banco Nacional de Desenvolvimento Econômico e Social

MCTI | Conselho Nacional de Desenvolvimento Científico e Tecnológico

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

Link

https://journals.asm.org/doi/pdf/10.1128/AAC.02222-17

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1. Isoniazid metal complex reactivity and insights for a novel anti-tuberculosis drug design

2. An inorganic iron complex that inhibits wild-type and an isoniazid-resistant mutant 2-trans-enoyl-ACP (CoA) reductase from Mycobacterium tuberculosis