Docking simulations and QM/MM studies between isoniazid prodrug, catalase-peroxidase (KatG) and S315T mutant from Mycobacterium tuberculosis
نویسندگان
چکیده
†Departamento de Quı́mica, Universidade Federal de Lavras—UFLA, Campus Universitário, Lavras, Caixa Postal 3037, Lavras, MG CEP: 37200-000, Brazil ‡Centro Brasileiro de Pesquisas Fı́sicas (CBPF), Rua Dr. Xavier Sigaud, 150, Urca, Rio de janeiro, RJ 22290-180, Brazil {Departamento de Quı́mica Orgânica, Instituto de Quı́mica, Universidade Federal do Rio de Janeiro, Ilha do Fundão, CT, Bl. A, Lab. 609, Rio de Janeiro, RJ 21949-900, Brazil §LEEM Fı́sico-Quı́mica, Instituto de Quı́mica, Universidade de Brası́lia—UnB, Cidade Universitária, Campus Darcy Ribeiro, Brası́lia, CEP 70919-970-DF, Brazil
منابع مشابه
Reduced affinity for Isoniazid in the S315T mutant of Mycobacterium tuberculosis KatG is a key factor in antibiotic resistance.
Catalase-peroxidase (KatG) from Mycobacterium tuberculosis is responsible for the activation of the antitubercular drug isonicotinic acid hydrazide (INH) and is important for survival of M. tuberculosis in macrophages. Characterization of the structure and catalytic mechanism of KatG is being pursued to provide insights into drug (INH) resistance in M. tuberculosis. Site-directed mutagenesis wa...
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Altered drug binding may be an important factor in isoniazid (INH) resistance, rather than major changes in the enzyme’s activity as a catalase or peroxidase (KatG). The identification of structural or functional defects in the mutant KatGs responsible for INH resistance remains as an area to be explored. In this connection, the differences in the binding affinity between wild-type (WT) and mut...
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Isoniazid, is the only antituberculous drug for which the relation between lack of virulence and acquisition of resistance was associated. INH-resistant mutants were shown to contain defective katG gene. Classical studies showed that INH-resistant south Indian isolates have lower virulence in guinea pigs and higher susceptibility to H2O2. It is of interest to assess the virulence in south India...
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Isoniazid is a first-line antibiotic used in the treatment of infections caused by Mycobacterium tuberculosis. Isoniazid is a prodrug requiring oxidative activation by the catalase-peroxidase hemoprotein, KatG. Resistance to isoniazid can be obtained by point mutations in the katG gene, with one of the most common being a threonine-for-serine substitution at position 315 (S315T). The S315T muta...
متن کاملIsoniazid activation defects in recombinant Mycobacterium tuberculosis catalase-peroxidase (KatG) mutants evident in InhA inhibitor production.
Mycobacterium tuberculosis KatG catalyzes the activation of the antitubercular agent isoniazid to yield an inhibitor targeting enoyl reductase (InhA). However, no firm biochemical link between many KatG variants and isoniazid resistance has been established. In the present study, six distinct KatG variants identified in clinical Mycobacterium tuberculosis isolates resistant to isoniazid were ge...
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