Pyrazinamide: Difference between revisions
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Pyrazinamide diffuses into the granuloma of M. tuberculosis, where the tuberculosis enzyme pyrazinamidase converts pyrazinamide to the active form pyrazinoic acid.<ref name="a15">PMID:26218737</ref> Under acidic conditions of pH 5 to 6, the pyrazinoic acid that slowly leaks out converts to the protonated conjugate acid, which is thought to diffuse easily back into the bacilli and accumulate. The net effect is that more pyrazinoic acid accumulates inside the bacillus at acid pH than at neutral pH.<ref name="a15">PMID:26218737</ref><ref name="a16">PMID:12701830</ref> | Pyrazinamide diffuses into the granuloma of M. tuberculosis, where the tuberculosis enzyme pyrazinamidase converts pyrazinamide to the active form pyrazinoic acid.<ref name="a15">PMID:26218737</ref> Under acidic conditions of pH 5 to 6, the pyrazinoic acid that slowly leaks out converts to the protonated conjugate acid, which is thought to diffuse easily back into the bacilli and accumulate. The net effect is that more pyrazinoic acid accumulates inside the bacillus at acid pH than at neutral pH.<ref name="a15">PMID:26218737</ref><ref name="a16">PMID:12701830</ref> | ||
'''Drug resistance mechanism of PncA in ''Mycobacterium Tuberculosis''<ref>doi 10.1080/07391102.2012.759885</ref>''' | |||
Tuberculosis continues to be a global health threat. <scene name='Journal:JBSD:11/Cv/6'>Pyrazinamide (PZA)</scene> is an important first-line drug in multidrug-resistant tuberculosis treatment. The emergence of strains resistant to pyrazinamide represents an important public health problem, as both first- and second-line treatment regimens include pyrazinamide. It becomes toxic to ''Mycobacterium tuberculosis'' when converted to pyrazinoic acid by the <scene name='Journal:JBSD:11/Cv/5'>bacterial pyrazinamidase (PncA) enzyme</scene>. PZA resistance is caused mainly by the loss of enzyme activity by mutation, the mechanism of resistance is not completely understood. In our studies, we analysed three mutations (D8G, S104R and C138Y) of PncA which are resistance for PZA. Binding pocket analysis solvent accessibility analysis, molecular docking and interaction analysis were performed to understand the interaction behaviour of mutant enzymes with PZA. Molecular dynamics simulations were conducted to understand the three dimensional conformational behaviour of <scene name='Journal:JBSD:11/Cv/3'>native</scene> and mutants PncA. Our analysis clearly indicates that the mutation (<scene name='Journal:JBSD:11/Cv/8'>D8G</scene>, <scene name='Journal:JBSD:11/Cv/9'>S104R</scene> and <scene name='Journal:JBSD:11/Cv/10'>C138Y</scene>) in PncA is responsible for rigid binding cavity which in turns abolishes conversion of PZA to its active form and is the sole reason for PZA resistance. Excessive hydrogen bonding between PZA binding cavity residues and their neighboring residues are the reason of rigid binding cavity during simulation. We present an exhaustive analysis of the binding-site flexibility and its 3D conformations that may serve as new starting points for structure-based drug design and helps there researchers to design new inhibitor with consideration of rigid criterion of binding residues due to mutation of this essential target. | |||
</StructureSection> | </StructureSection> | ||
== References == | == References == | ||
<references/> | <references/> | ||
Revision as of 16:30, 1 January 2024
Pyrazinamide is a medication used to treat tuberculosis.[1] For active tuberculosis, it is often used with rifampicin, isoniazid, and either streptomycin or ethambutol.[2] It is not generally recommended for the treatment of latent tuberculosis.[1] See also Pyrazinamide. Pyrazinamide diffuses into the granuloma of M. tuberculosis, where the tuberculosis enzyme pyrazinamidase converts pyrazinamide to the active form pyrazinoic acid.[3] Under acidic conditions of pH 5 to 6, the pyrazinoic acid that slowly leaks out converts to the protonated conjugate acid, which is thought to diffuse easily back into the bacilli and accumulate. The net effect is that more pyrazinoic acid accumulates inside the bacillus at acid pH than at neutral pH.[3][4] Drug resistance mechanism of PncA in Mycobacterium Tuberculosis[5] Tuberculosis continues to be a global health threat. is an important first-line drug in multidrug-resistant tuberculosis treatment. The emergence of strains resistant to pyrazinamide represents an important public health problem, as both first- and second-line treatment regimens include pyrazinamide. It becomes toxic to Mycobacterium tuberculosis when converted to pyrazinoic acid by the . PZA resistance is caused mainly by the loss of enzyme activity by mutation, the mechanism of resistance is not completely understood. In our studies, we analysed three mutations (D8G, S104R and C138Y) of PncA which are resistance for PZA. Binding pocket analysis solvent accessibility analysis, molecular docking and interaction analysis were performed to understand the interaction behaviour of mutant enzymes with PZA. Molecular dynamics simulations were conducted to understand the three dimensional conformational behaviour of and mutants PncA. Our analysis clearly indicates that the mutation (, and ) in PncA is responsible for rigid binding cavity which in turns abolishes conversion of PZA to its active form and is the sole reason for PZA resistance. Excessive hydrogen bonding between PZA binding cavity residues and their neighboring residues are the reason of rigid binding cavity during simulation. We present an exhaustive analysis of the binding-site flexibility and its 3D conformations that may serve as new starting points for structure-based drug design and helps there researchers to design new inhibitor with consideration of rigid criterion of binding residues due to mutation of this essential target. |
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ReferencesReferences
- ↑ 1.0 1.1 "Pyrazinamide". The American Society of Health-System Pharmacists. Archived from the original on 20 December 2016. Retrieved 8 December 2016.
- ↑ World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary. World Health Organization. pp. 136, 140, 594, 608. hdl:10665/44053. ISBN 978-9241547659.
- ↑ 3.0 3.1 Whitfield MG, Soeters HM, Warren RM, York T, Sampson SL, Streicher EM, van Helden PD, van Rie A. A Global Perspective on Pyrazinamide Resistance: Systematic Review and Meta-Analysis. PLoS One. 2015 Jul 28;10(7):e0133869. PMID:26218737 doi:10.1371/journal.pone.0133869
- ↑ Zhang Y, Mitchison D. The curious characteristics of pyrazinamide: a review. Int J Tuberc Lung Dis. 2003 Jan;7(1):6-21 PMID:12701830
- ↑ Rajendran V, Sethumadhavan R. Drug resistance mechanism of PncA in Mycobacterium tuberculosis. J Biomol Struct Dyn. 2013 Feb 6. PMID:23383724 doi:10.1080/07391102.2012.759885