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

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Abstract

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.

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Acknowledgments

Fundação Araucária (convênio 147/14), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Centro Nacional de Processamento de Alto Desempenho-Sao Paulo (CENAPAD-SP) (proj512) and Laboratório Nacional de Computação Científica (LNCC).

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Authors and Affiliations

  1. Departamento de Bioquímica, Universidade Estadual de Maringá (UEM), Av. Colombo, 5790, Maringá, PR, Brazil

    Arethusa Lobo Pimentel & Flavio Augusto Vicente Seixas

  2. Departamento de Análises Clínicas e Biomedicina, Universidade Estadual de Maringá (UEM), Av. Colombo, 5790, Maringá, PR, Brazil

    Regiane Bertin de Lima Scodro, Katiany Rizzieri Caleffi-Ferracioli, Vera Lúcia Dias Siqueira, Paula Aline Zanetti Campanerut-Sá, Luciana Dias Ghiraldi Lopes, Aryadne Larissa de Almeida & Rosilene Fressatti Cardoso

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  1. Arethusa Lobo Pimentel
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  2. Regiane Bertin de Lima Scodro
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  9. Flavio Augusto Vicente Seixas
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Correspondence to Flavio Augusto Vicente Seixas.

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Pimentel, A.L., de Lima Scodro, R.B., Caleffi-Ferracioli, K.R. et al. Mutations in catalase-peroxidase KatG from isoniazid resistant Mycobacterium tuberculosis clinical isolates: insights from molecular dynamics simulations. J Mol Model 23, 121 (2017). https://doi.org/10.1007/s00894-017-3290-3

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