Structural Dynamics Behind Clinical Mutants of PncA-Asp12Ala, Pro54Leu, and His57Pro of Mycobacterium tuberculosis Associated With Pyrazinamide Resistance
Pyrazinamide (PZA) is one of the main FDA approved drugs to be used as the first line of defense against Mycobacterium Tuberculosis (MTB). It is activated into pyrazinoic acid (POA) via MTB's pncA gene-encoded pyrazinamidase (PZase). Mutations are most commonly responsible for PZA-resistance in...
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Frontiers Media S.A.
2019-12-01
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| Series: | Frontiers in Bioengineering and Biotechnology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fbioe.2019.00404/full |
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| author | Aamir Mehmood Muhammad Tahir Khan Aman Chandra Kaushik Anwar Sheed Khan Muhammad Irfan Dong-Qing Wei |
| author_facet | Aamir Mehmood Muhammad Tahir Khan Aman Chandra Kaushik Anwar Sheed Khan Muhammad Irfan Dong-Qing Wei |
| author_sort | Aamir Mehmood |
| collection | DOAJ |
| description | Pyrazinamide (PZA) is one of the main FDA approved drugs to be used as the first line of defense against Mycobacterium Tuberculosis (MTB). It is activated into pyrazinoic acid (POA) via MTB's pncA gene-encoded pyrazinamidase (PZase). Mutations are most commonly responsible for PZA-resistance in nearly 70% of the resistant samples. In the present work, MTB positive samples were chosen for PZA drug susceptibility testing (DST) against critical concentration (100 ug/ml) of PZA. The resistant samples were subjected to pncA sequencing. As a result, 36 various mutations have been observed in the PZA resistant samples, uploaded to the NCBI (GeneBank accession no. MH461111). Here we report the mechanism of PZA resistance behind the three mutants (MTs), Asp12Ala, Pro54Leu, and His57Pro in comparison with the wild type (WT) through molecular dynamics simulation to unveil how these mutations affect the overall conformational stability. The post-simulation analyses revealed notable deviations as compared to the WT structure. Molecular docking studies of PZA with MTs and WT, pocket volume inspection and overall shape complementarity analysis confirmed the deleterious nature of these mutations and gave an insight into the mechanism behind PZA-resistance. These analyses provide vital information regarding MTB drug resistance and could be extremely useful in therapy management and overcoming its global burden. |
| first_indexed | 2024-12-13T01:18:35Z |
| format | Article |
| id | doaj.art-a8fcae9137fc44f5958f9cce2c096628 |
| institution | Directory Open Access Journal |
| issn | 2296-4185 |
| language | English |
| last_indexed | 2024-12-13T01:18:35Z |
| publishDate | 2019-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Bioengineering and Biotechnology |
| spelling | doaj.art-a8fcae9137fc44f5958f9cce2c0966282022-12-22T00:04:17ZengFrontiers Media S.A.Frontiers in Bioengineering and Biotechnology2296-41852019-12-01710.3389/fbioe.2019.00404494843Structural Dynamics Behind Clinical Mutants of PncA-Asp12Ala, Pro54Leu, and His57Pro of Mycobacterium tuberculosis Associated With Pyrazinamide ResistanceAamir Mehmood0Muhammad Tahir Khan1Aman Chandra Kaushik2Anwar Sheed Khan3Muhammad Irfan4Dong-Qing Wei5The State Key Laboratory of Microbial Metabolism, College of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Bioinformatics and Biosciences, Capital University of Science and Technology, Islamabad, PakistanWuxi School of Medicine, Jiangnan University, Wuxi, ChinaDepartment of Microbiology, Kohat University of Science and Technology, Kohat, PakistanDepartment of Microbiology and Cell Science, Genetics Institute and Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL, United StatesThe State Key Laboratory of Microbial Metabolism, College of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, ChinaPyrazinamide (PZA) is one of the main FDA approved drugs to be used as the first line of defense against Mycobacterium Tuberculosis (MTB). It is activated into pyrazinoic acid (POA) via MTB's pncA gene-encoded pyrazinamidase (PZase). Mutations are most commonly responsible for PZA-resistance in nearly 70% of the resistant samples. In the present work, MTB positive samples were chosen for PZA drug susceptibility testing (DST) against critical concentration (100 ug/ml) of PZA. The resistant samples were subjected to pncA sequencing. As a result, 36 various mutations have been observed in the PZA resistant samples, uploaded to the NCBI (GeneBank accession no. MH461111). Here we report the mechanism of PZA resistance behind the three mutants (MTs), Asp12Ala, Pro54Leu, and His57Pro in comparison with the wild type (WT) through molecular dynamics simulation to unveil how these mutations affect the overall conformational stability. The post-simulation analyses revealed notable deviations as compared to the WT structure. Molecular docking studies of PZA with MTs and WT, pocket volume inspection and overall shape complementarity analysis confirmed the deleterious nature of these mutations and gave an insight into the mechanism behind PZA-resistance. These analyses provide vital information regarding MTB drug resistance and could be extremely useful in therapy management and overcoming its global burden.https://www.frontiersin.org/article/10.3389/fbioe.2019.00404/fulldrug resistancesimulationmutationsPZAMTB |
| spellingShingle | Aamir Mehmood Muhammad Tahir Khan Aman Chandra Kaushik Anwar Sheed Khan Muhammad Irfan Dong-Qing Wei Structural Dynamics Behind Clinical Mutants of PncA-Asp12Ala, Pro54Leu, and His57Pro of Mycobacterium tuberculosis Associated With Pyrazinamide Resistance Frontiers in Bioengineering and Biotechnology drug resistance simulation mutations PZA MTB |
| title | Structural Dynamics Behind Clinical Mutants of PncA-Asp12Ala, Pro54Leu, and His57Pro of Mycobacterium tuberculosis Associated With Pyrazinamide Resistance |
| title_full | Structural Dynamics Behind Clinical Mutants of PncA-Asp12Ala, Pro54Leu, and His57Pro of Mycobacterium tuberculosis Associated With Pyrazinamide Resistance |
| title_fullStr | Structural Dynamics Behind Clinical Mutants of PncA-Asp12Ala, Pro54Leu, and His57Pro of Mycobacterium tuberculosis Associated With Pyrazinamide Resistance |
| title_full_unstemmed | Structural Dynamics Behind Clinical Mutants of PncA-Asp12Ala, Pro54Leu, and His57Pro of Mycobacterium tuberculosis Associated With Pyrazinamide Resistance |
| title_short | Structural Dynamics Behind Clinical Mutants of PncA-Asp12Ala, Pro54Leu, and His57Pro of Mycobacterium tuberculosis Associated With Pyrazinamide Resistance |
| title_sort | structural dynamics behind clinical mutants of pnca asp12ala pro54leu and his57pro of mycobacterium tuberculosis associated with pyrazinamide resistance |
| topic | drug resistance simulation mutations PZA MTB |
| url | https://www.frontiersin.org/article/10.3389/fbioe.2019.00404/full |
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