Mutations in catalase-peroxidase KatG from isoniazid resistant Mycobacterium tuberculosis clinical isolates: insights from molecular dynamics simulations

The current multidrug therapy for tuberculosis (TB) is based on the use of isoniazid (INH) in combination with other antibiotics such as rifampin, ethambutol and pyrazinamide. Literature reports have shown that Mycobacterium tuberculosis , the causative agent of TB, has become resistant to this trea...

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Bibliographic Details
Published in:Journal of molecular modeling 2017-04, Vol.23 (4), p.121-6, Article 121
Main Authors: Pimentel, Arethusa Lobo, de Lima Scodro, Regiane Bertin, Caleffi-Ferracioli, Katiany Rizzieri, Siqueira, Vera Lúcia Dias, Campanerut-Sá, Paula Aline Zanetti, Lopes, Luciana Dias Ghiraldi, de Almeida, Aryadne Larissa, Cardoso, Rosilene Fressatti, Seixas, Flavio Augusto Vicente
Format: Article
Language:English
Subjects:
Antibiotics
Catalase
Characterization and Evaluation of Materials
Chemistry
Chemistry and Materials Science
Computer Appl. in Life Sciences
Computer Applications in Chemistry
Molecular dynamics
Molecular Medicine
Mutation
Original Paper
Peroxidase
Theoretical and Computational Chemistry
Tuberculosis
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Summary:The current multidrug therapy for tuberculosis (TB) is based on the use of isoniazid (INH) in combination with other antibiotics such as rifampin, ethambutol and pyrazinamide. Literature reports have shown that Mycobacterium tuberculosis , the causative agent of TB, has become resistant to this treatment by means of point mutations in the target enzymes of these drugs, such as catalase-peroxidase (KatG). By means of equilibrium molecular dynamics in the presence of the ligand, this work evaluated ten point mutations described in the enzyme KatG that are related to resistance to INH . The results showed that the resistance mechanism is related to stereochemical modifications at the N-terminal domain of the protein, which restrict INH access to its catalytic site, not involving mechanisms of electrostatic nature. These results show insights that can be useful for the identification of new anti-TB drugs which may be able to circumvent this mechanism of resistance.
ISSN:1610-2940
0948-5023
DOI:10.1007/s00894-017-3290-3