Mutations in Catalase-peroxidase KatG from Isoniazid Resistant Mycobacterium Tuberculosis Clinical Isolates: Insights from Molecular Dynamics Simulations

Overview

Journal J Mol Model

Publisher Springer

Specialty Molecular Biology

Date 2017 Mar 18

PMID 28303436

Citations 4

Authors

Arethusa Lobo Pimentel

Regiane Bertin de Lima Scodro

Katiany Rizzieri Caleffi-Ferracioli

Vera Lucia Dias Siqueira

Paula Aline Zanetti Campanerut-Sa

Luciana Dias Ghiraldi Lopes

Aryadne Larissa de Almeida

Rosilene Fressatti Cardoso

Flavio Augusto Vicente Seixas

Affiliations

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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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References

Purohit R, Rajendran V, Sethumadhavan R . Relationship between mutation of serine residue at 315th position in M. tuberculosis catalase-peroxidase enzyme and Isoniazid susceptibility: an in silico analysis. J Mol Model. 2010; 17(4):869-77. DOI: 10.1007/s00894-010-0785-6. View

Jeeves R, Marriott A, Pullan S, Hatch K, Allnutt J, Freire-Martin I . Mycobacterium tuberculosis Is Resistant to Isoniazid at a Slow Growth Rate by Single Nucleotide Polymorphisms in katG Codon Ser315. PLoS One. 2015; 10(9):e0138253. PMC: 4575197. DOI: 10.1371/journal.pone.0138253. View

Seixas F, Santini T, Moura V, Gandra E . Evaluation of the (haem)Fe--Nepsilon(2)(HisF8) bond distances from haemoglobin structures deposited in the Protein Data Bank. Acta Crystallogr D Biol Crystallogr. 2008; 64(Pt 9):971-6. DOI: 10.1107/S0907444908022208. View

Bertrand T, Eady N, Jones J, Jesmin , Nagy J, Jamart-Gregoire B . Crystal structure of Mycobacterium tuberculosis catalase-peroxidase. J Biol Chem. 2004; 279(37):38991-9. DOI: 10.1074/jbc.M402382200. View

Cardoso R, Cooksey R, Morlock G, Barco P, Cecon L, Forestiero F . Screening and characterization of mutations in isoniazid-resistant Mycobacterium tuberculosis isolates obtained in Brazil. Antimicrob Agents Chemother. 2004; 48(9):3373-81. PMC: 514764. DOI: 10.1128/AAC.48.9.3373-3381.2004. View

Blanchard J . Molecular mechanisms of drug resistance in Mycobacterium tuberculosis. Annu Rev Biochem. 1996; 65:215-39. DOI: 10.1146/annurev.bi.65.070196.001243. View

Degen T, Bregenzer T . [The treatment of tuberculosis]. Praxis (Bern 1994). 2016; 105(8):457-61. DOI: 10.1024/1661-8157/a002322. View

de Beer T, Berka K, Thornton J, Laskowski R . PDBsum additions. Nucleic Acids Res. 2013; 42(Database issue):D292-6. PMC: 3965036. DOI: 10.1093/nar/gkt940. View

Zoete V, Cuendet M, Grosdidier A, Michielin O . SwissParam: a fast force field generation tool for small organic molecules. J Comput Chem. 2011; 32(11):2359-68. DOI: 10.1002/jcc.21816. View

10.

Kumari R, Kumar R, Lynn A . g_mmpbsa--a GROMACS tool for high-throughput MM-PBSA calculations. J Chem Inf Model. 2014; 54(7):1951-62. DOI: 10.1021/ci500020m. View

11.

Vidossich P, Loewen P, Carpena X, Fiorin G, Fita I, Rovira C . Binding of the antitubercular pro-drug isoniazid in the heme access channel of catalase-peroxidase (KatG). A combined structural and metadynamics investigation. J Phys Chem B. 2014; 118(11):2924-31. DOI: 10.1021/jp4123425. View

12.

da Costa A, Pauli I, Dorn M, Schroeder E, Zhan C, Norberto de Souza O . Conformational changes in 2-trans-enoyl-ACP (CoA) reductase (InhA) from M. tuberculosis induced by an inorganic complex: a molecular dynamics simulation study. J Mol Model. 2011; 18(5):1779-90. DOI: 10.1007/s00894-011-1200-7. View

13.

Banerjee A, DUBNAU E, Quemard A, Balasubramanian V, Um K, Wilson T . inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science. 1994; 263(5144):227-30. DOI: 10.1126/science.8284673. View

14.

Phillips J, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E . Scalable molecular dynamics with NAMD. J Comput Chem. 2005; 26(16):1781-802. PMC: 2486339. DOI: 10.1002/jcc.20289. View

15.

Pacheco Homem D, Flores Jr R, Tosqui P, de Castro Rozada T, Basso E, Gasparotto Jr A . Homology modeling of dihydrofolate reductase from T. gondii bonded to antagonists: molecular docking and molecular dynamics simulations. Mol Biosyst. 2013; 9(6):1308-15. DOI: 10.1039/c3mb25530a. View

16.

Zhao X, Hersleth H, Zhu J, Andersson K, Magliozzo R . Access channel residues Ser315 and Asp137 in Mycobacterium tuberculosis catalase-peroxidase (KatG) control peroxidatic activation of the pro-drug isoniazid. Chem Commun (Camb). 2013; 49(99):11650-2. PMC: 3872143. DOI: 10.1039/c3cc47022a. View

17.

Unissa A, Selvakumar N, Narayanan S, Suganthi C, Hanna L . Investigation of Ser315 substitutions within katG gene in isoniazid-resistant clinical isolates of Mycobacterium tuberculosis from south India. Biomed Res Int. 2015; 2015:257983. PMC: 4324114. DOI: 10.1155/2015/257983. View

18.

van Doorn H, Kuijper E, van der Ende A, Welten A, van Soolingen D, de Haas P . The susceptibility of Mycobacterium tuberculosis to isoniazid and the Arg-->Leu mutation at codon 463 of katG are not associated. J Clin Microbiol. 2001; 39(4):1591-4. PMC: 87976. DOI: 10.1128/JCM.39.4.1591-1594.2001. View

19.

Rodrigues L, Machado D, Couto I, Amaral L, Viveiros M . Contribution of efflux activity to isoniazid resistance in the Mycobacterium tuberculosis complex. Infect Genet Evol. 2011; 12(4):695-700. DOI: 10.1016/j.meegid.2011.08.009. View

20.

Schmidtke P, Bidon-Chanal A, Luque F, Barril X . MDpocket: open-source cavity detection and characterization on molecular dynamics trajectories. Bioinformatics. 2011; 27(23):3276-85. DOI: 10.1093/bioinformatics/btr550. View