title: Mutations in catalase-peroxidase KatG from isoniazid resistant Mycobacterium tuberculosis clinical isolates: insights from molecular dynamics simulations.
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.
authors.affiliation: Departamento de Bioquímica, Universidade Estadual de Maringá (UEM), Av. Colombo, 5790, Maringá, PR, Brazil.
authors.forename: Arethusa Lobo
authors.initials: AL
authors.lastname: Pimentel
authors.affiliation: Departamento de Análises Clínicas e Biomedicina, Universidade Estadual de Maringá (UEM), Av. Colombo, 5790, Maringá, PR, Brazil.
authors.forename: Regiane Bertin
authors.initials: RB
authors.lastname: de Lima Scodro
authors.affiliation: Departamento de Análises Clínicas e Biomedicina, Universidade Estadual de Maringá (UEM), Av. Colombo, 5790, Maringá, PR, Brazil.
authors.forename: Katiany Rizzieri
authors.initials: KR
authors.lastname: Caleffi-Ferracioli
authors.affiliation: Departamento de Análises Clínicas e Biomedicina, Universidade Estadual de Maringá (UEM), Av. Colombo, 5790, Maringá, PR, Brazil.
authors.forename: Vera Lúcia Dias
authors.initials: VL
authors.lastname: Siqueira
authors.affiliation: Departamento de Análises Clínicas e Biomedicina, Universidade Estadual de Maringá (UEM), Av. Colombo, 5790, Maringá, PR, Brazil.
authors.forename: Paula Aline Zanetti
authors.initials: PA
authors.lastname: Campanerut-Sá
authors.affiliation: Departamento de Análises Clínicas e Biomedicina, Universidade Estadual de Maringá (UEM), Av. Colombo, 5790, Maringá, PR, Brazil.
authors.forename: Luciana Dias Ghiraldi
authors.initials: LD
authors.lastname: Lopes
authors.affiliation: Departamento de Análises Clínicas e Biomedicina, Universidade Estadual de Maringá (UEM), Av. Colombo, 5790, Maringá, PR, Brazil.
authors.forename: Aryadne Larissa
authors.initials: AL
authors.lastname: de Almeida
authors.affiliation: Departamento de Análises Clínicas e Biomedicina, Universidade Estadual de Maringá (UEM), Av. Colombo, 5790, Maringá, PR, Brazil.
authors.forename: Rosilene Fressatti
authors.initials: RF
authors.lastname: Cardoso
authors.affiliation: Departamento de Bioquímica, Universidade Estadual de Maringá (UEM), Av. Colombo, 5790, Maringá, PR, Brazil. favseixas@uem.br.
authors.forename: Flavio Augusto Vicente
authors.identifier: http://orcid.org/0000-0002-0117-6919
authors.initials: FA
authors.lastname: Seixas
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D002374:Catalase / Q000037:antagonists & inhibitors / Q000235:genetics*; D020134:Catalytic Domain; D024881:Drug Resistance, Bacterial; D007538:Isoniazid / Q000494:pharmacology*; D008024:Ligands; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D008024:Ligands; D002374:Catalase; C480353:katG protein, Mycobacterium tuberculosis; D007538:Isoniazid
keywords: Catalase-peroxidase; Drug resistance; Isoniazid; Mycobacterium tuberculosis