Structural and Dynamic Insights into the W68L, L85P, and T87A Mutations of Mycobacterium tuberculosis Inducing Resistance to Pyrazinamide
Abstract
:1. Introduction
2. Material and Methods
2.1. Retrieval of PZase and PZA
2.2. Molecular Docking
2.3. Molecular Dynamics Simulation
2.4. Principal Component Analysis
2.5. Free Energy Landscape (FEL)
2.6. Binding Affinity Calculations
3. Results and Discussion
3.1. Stability Evaluation of the Wildtype and Mutant Complexes
3.2. Determination of Structural Compactness as Rg (Radius of Gyration)
3.3. Residual Flexibility (RMSF) Estimation
3.4. Hydrogen Bonding Analysis
3.5. Principle Component Analysis (PCA) and Free Energy Landscape (FEL)
3.6. Free Energy Landscape (FEL) Analysis
3.7. Free Energy Calculations
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Glickman, M.S.; Jacobs, W.R. Microbial Pathogenesis of Mycobacterium tuberculosis: Dawn of a Discipline. Cell 2001, 104, 477–485. [Google Scholar] [CrossRef] [Green Version]
- WHO. Global Tuberculosis Report 2020: Executive Summary; WHO: Geneva, Switzerland, 2020.
- Al-Mutairi, N.M.; Ahmad, S.; Mokaddas, E. Increasing prevalence of resistance to second-line drugs among multidrug-resistant Mycobacterium tuberculosis isolates in Kuwait. Sci. Rep. 2021, 11, 1–9. [Google Scholar] [CrossRef]
- Konno, K.; Feldmann, F.M.; McDermott, W. Pyrazinamide susceptibility and amidase activity of tubercle bacilli. Am. Rev. Respir. Dis. 1967, 95, 461–469. [Google Scholar] [CrossRef] [PubMed]
- Gopal, P.; Nartey, W.; Ragunathan, P.; Sarathy, J.; Kaya, F.; Yee, M.; Setzer, C.; Manimekalai, M.S.S.; Dartois, V.; Grüber, G.; et al. Pyrazinoic Acid Inhibits Mycobacterial Coenzyme A Biosynthesis by Binding to Aspartate Decarboxylase PanD. ACS Infect. Dis. 2017, 3, 807–819. [Google Scholar] [CrossRef] [PubMed]
- Shi, W.; Zhang, X.; Jiang, X.; Yuan, H.; Lee, J.S.; Barry, C.E.; Wang, H.; Zhang, W.; Zhang, Y. Pyrazinamide Inhibits Trans-Translation in Mycobacterium tuberculosis. Science 2011, 333, 1630–1632. [Google Scholar] [CrossRef] [Green Version]
- Scorpio, A.; Lindholm-Levy, P.; Heifets, L.; Gilman, R.; Siddiqi, S.; Cynamon, M.; Zhang, Y. Characterization of pncA mutations in pyrazinamide-resistant Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 1997, 41, 540–543. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Scorpio, A.; Zhang, Y. Mutations in pncA, a gene encoding pyrazinamidase/nicotinamidase, cause resistance to the antituberculous drug pyrazinamide in tubercle bacillus. Nat. Med. 1996, 2, 662–667. [Google Scholar] [CrossRef]
- Cheng, S.-J.; Thibert, L.; Sanchez, T.; Heifets, L.; Zhang, Y. PncA Mutations as a Major Mechanism of Pyrazinamide Resistance in Mycobacterium tuberculosis: Spread of a Monoresistant Strain in Quebec, Canada. Antimicrob. Agents Chemother. 2000, 44, 528–532. [Google Scholar] [CrossRef] [Green Version]
- Zimic, M.; Sheen, P.; Quiliano, M.; Gutierrez, A.; Gilman, R.H. Peruvian and globally reported amino acid substitutions on the Mycobacterium tuberculosis pyrazinamidase suggest a conserved pattern of mutations associated to pyrazinamide resistance. Infect. Genet. Evol. 2010, 10, 346–349. [Google Scholar] [CrossRef] [Green Version]
- Werngren, J.; Sturegård, E.; Juréen, P.; Ängeby, K.; Hoffner, S.; Schön, T. Reevaluation of the critical concentration for drug susceptibility testing of Mycobacterium tuberculosis against pyrazinamide using wild-type MIC distributions and pncA gene sequencing. Antimicrob. Agents Chemother. 2012, 56, 1253–1257. [Google Scholar] [CrossRef] [Green Version]
- Stoffels, K.; Mathys, V.; Fauville-Dufaux, M.; Wintjens, R.; Bifani, P. Systematic Analysis of Pyrazinamide-Resistant Spontaneous Mutants and Clinical Isolates of Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 2012, 56, 5186–5193. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Somoskovi, A.; Dormandy, J.; Parsons, L.M.; Kaswa, M.; Goh, K.S.; Rastogi, N.; Salfinger, M. Sequencing of the pncA Gene in Members of the Mycobacterium tuberculosis Complex Has Important Diagnostic Applications: Identification of a Species-Specific pncA Mutation in “Mycobacterium canettii” and the Reliable and Rapid Predictor of Pyrazinamide Resistance. J. Clin. Microbiol. 2007, 45, 595–599. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bishop, K.S.; Blumberg, L.; Trollip, A.P.; Smith, A.N.; Roux, L.; York, D.F.; Kiepiela, P. Characterisation of the pncA gene in Mycobacterium tuberculosis isolates from Gauteng, South Africa. Int. J. Tuberc. Lung Dis. 2001, 5, 952–957. [Google Scholar] [PubMed]
- Huang, T.-S.; Lee, S.S.-J.; Tu, H.-Z.; Huang, W.-K.; Chen, Y.-S.; Huang, C.-K.; Wann, S.-R.; Lin, H.-H.; Liu, Y.-C. Correlation between Pyrazinamide Activity and pncA Mutations in Mycobacterium tuberculosis Isolates in Taiwan. Antimicrob. Agents Chemother. 2003, 47, 3672–3673. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, J.; Shi, W.; Zhang, S.; Hao, X.; Maslov, D.; Shur, K.V.; Bekker, O.B.; Danilenko, V.N.; Zhang, Y. Mutations in Efflux Pump Rv1258c (Tap) Cause Resistance to Pyrazinamide, Isoniazid, and Streptomycin in M. tuberculosis. Front. Microbiol. 2019, 10, 216. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, S.; Chen, J.; Shi, W.; Liu, W.; Zhang, W.; Zhang, Y. Mutations in panD encoding aspartate decarboxylase are associated with pyrazinamide resistance in Mycobacterium tuberculosis. Emerg. Microbes Infect. 2013, 2, 1–5. [Google Scholar] [CrossRef]
- Zhang, Y.; Shi, W.; Zhang, W.; Mitchison, D. Mechanisms of Pyrazinamide Action and Resistance. Mol. Genet. Mycobact. 2014, 2, 479–491. [Google Scholar] [CrossRef] [Green Version]
- Kohanski, M.A.; DePristo, M.A.; Collins, J.J. Sublethal Antibiotic Treatment Leads to Multidrug Resistance via Radical-Induced Mutagenesis. Mol. Cell 2010, 37, 311–320. [Google Scholar] [CrossRef] [Green Version]
- Victor, T.C.; Van Helden, P.D.; Warren, R. Prediction of Drug Resistance in M. tuberculosis: Molecular Mechanisms, Tools, and Applications. IUBMB Life 2002, 53, 231–237. [Google Scholar] [CrossRef] [PubMed]
- Ramaswamy, S.; Musser, J. Molecular genetic basis of antimicrobial agent resistance inMycobacterium tuberculosis: 1998 update. Tuber. Lung Dis. 1998, 79, 3–29. [Google Scholar] [CrossRef] [Green Version]
- Khan, A.; Khan, S.; Saleem, S.; Nizam-Uddin, N.; Mohammad, A.; Khan, T.; Ahmad, S.; Arshad, M.; Ali, S.S.; Suleman, M. Immunogenomics Guided Design of Immunomodulatory Multi-Epitope Subunit Vaccine against the SARS-CoV-2 new Variants, and its Validation through in Silico Cloning and Immune Simulation. Comput. Biol. Med. 2021, 133, 104420. [Google Scholar] [CrossRef] [PubMed]
- Khan, A.; Zia, T.; Suleman, M.; Khan, T.; Ali, S.S.; Abbasi, A.A.; Mohammad, A.; Wei, D. Higher infectivity of the SARS-CoV-2 new variants is associated with K417N/T, E484K, and N501Y mutants: An insight from structural data. J. Cell. Physiol. 2021, 236, 7045–7057. [Google Scholar] [CrossRef] [PubMed]
- Khan, A.; Wei, D.-Q.; Kousar, K.; Abubaker, J.; Ahmad, S.; Ali, J.; Al-Mulla, F.; Ali, S.S.; Nizam-Uddin, N.; Sayaf, A.M. Preliminary Structural Data Revealed that the SARS-CoV-2 B.1.617 Variant’s RBD binds to ACE2 receptor stronger than the Wild Type to Enhance the Infectivity. ChemBioChem 2021, 22, 2641. [Google Scholar] [CrossRef] [PubMed]
- Khan, A.; Gui, J.; Ahmad, W.; Haq, I.; Shahid, M.; Khan, A.A.; Shah, A.; Khan, A.; Ali, L.; Anwar, Z.; et al. The SARS-CoV-2 B.1.618 variant slightly alters the spike RBD–ACE2 binding affinity and is an antibody escaping variant: A computational structural perspective. RSC Adv. 2021, 11, 30132–30147. [Google Scholar] [CrossRef]
- Khan, A.; Khan, T.; Ali, S.; Aftab, S.; Wang, Y.; Qiankun, W.; Khan, M.; Suleman, M.; Ali, S.; Heng, W. SARS-CoV-2 new variants: Characteristic features and impact on the efficacy of different vaccines. Biomed. Pharmacother. 2021, 143, 112176. [Google Scholar] [CrossRef]
- Khan, A.; Khan, M.T.; Saleem, S.; Junaid, M.; Ali, A.; Ali, S.S.; Khan, M.; Wei, D.-Q. Structural Insights into the mechanism of RNA recognition by the N-terminal RNA-binding domain of the SARS-CoV-2 nucleocapsid phosphoprotein. Comput. Struct. Biotechnol. J. 2020, 18, 2174–2184. [Google Scholar] [CrossRef] [PubMed]
- Khan, A.; Khan, M.; Saleem, S.; Babar, Z.; Ali, A.; Khan, A.A.; Sardar, Z.; Hamayun, F.; Ali, S.S.; Wei, D.-Q. Decoding the structure of RNA-dependent RNA-polymerase (RdRp), understanding the ancestral relationship and dispersion pattern of 2019 Wuhan Coronavirus. Res. Sq. 2020. [Google Scholar] [CrossRef]
- Khan, A.; Khan, M.; Saleem, S.; Babar, Z.; Ali, A.; Khan, A.A.; Sardar, Z.; Hamayun, F.; Ali, S.S.; Wei, D.-Q. Phylogenetic analysis and structural perspectives of RNA-dependent RNA-polymerase inhibition from SARS-CoV-2 with natural products. Interdiscip. Sci. Comput. Life Sci. 2020, 12, 335–348. [Google Scholar] [CrossRef]
- Khan, A.; Junaid, M.; Kaushik, A.C.; Ali, A.; Ali, S.S.; Mehmood, A.; Wei, D.-Q. Computational identification, characterization and validation of potential antigenic peptide vaccines from hrHPVs E6 proteins using immunoinformatics and computational systems biology approaches. PLoS ONE 2018, 13, e0196484. [Google Scholar] [CrossRef] [Green Version]
- Khan, A.; Ali, S.S.; Khan, M.T.; Saleem, S.; Ali, A.; Suleman, M.; Babar, Z.; Shafiq, A.; Khan, M.; Wei, D.-Q. Combined drug repurposing and virtual screening strategies with molecular dynamics simulation identified potent inhibitors for SARS-CoV-2 main protease (3CLpro). J. Biomol. Struct. Dyn. 2020, 39, 4659–4670. [Google Scholar] [CrossRef] [PubMed]
- Hussain, I.; Pervaiz, N.; Khan, A.; Saleem, S.; Shireen, H.; Wei, D.-Q.; Labrie, V.; Bao, Y.; Abbasi, A.A. Evolutionary and structural analysis of SARS-CoV-2 specific evasion of host immunity. Genes Immun. 2020, 21, 409–419. [Google Scholar] [CrossRef] [PubMed]
- Arnold, R.; Boonen, K.; Sun, M.G.; Kim, P.M. Computational analysis of interactomes: Current and future perspectives for bioinformatics approaches to model the host–pathogen interaction space. Methods 2012, 57, 508–518. [Google Scholar] [CrossRef] [PubMed]
- Squires, B.; Macken, C.; Garcia-Sastre, A.; Godbole, S.; Noronha, J.; Hunt, V.; Chang, R.; Larsen, C.N.; Klem, E.; Biersack, K.; et al. BioHealthBase: Informatics support in the elucidation of influenza virus host–pathogen interactions and virulence. Nucleic Acids Res. 2008, 36, D497–D503. [Google Scholar] [CrossRef] [PubMed]
- Sudha, G.; Nussinov, R.; Srinivasan, N. An overview of recent advances in structural bioinformatics of protein–protein interactions and a guide to their principles. Prog. Biophys. Mol. Biol. 2014, 116, 141–150. [Google Scholar] [CrossRef] [PubMed]
- Muneer, I.; Ahmad, S.; Naz, A.; Abbasi, S.W.; Alblihy, A.; Aloliqi, A.A.; Alkhayl, F.F.; Alrumaihi, F.; Ahmad, S.; El Bakri, Y. Discovery of Novel Inhibitors from Medicinal Plants for V-Domain Ig Suppressor of T-Cell Activation (VISTA). Front. Mol. Biosci. 2021, 8, 951. [Google Scholar] [CrossRef]
- Arif, R.; Ahmad, S.; Mustafa, G.; Mahrosh, H.S.; Ali, M.; Qamar, M.T.U.; Dar, H.R. Molecular Docking and Simulation Studies of Antidiabetic Agents Devised from Hypoglycemic Polypeptide-P of Momordica charantia. BioMed Res. Int. 2021, 2021, 1–15. [Google Scholar] [CrossRef]
- Altharawi, A.; Ahmad, S.; Alamri, M.A.; Qamar, M.T.U. Structural insight into the binding pattern and interaction mechanism of chemotherapeutic agents with Sorcin by docking and molecular dynamic simulation. Colloids Surf. B Biointerfaces 2021, 208, 112098. [Google Scholar] [CrossRef]
- Verma, H.; Nagar, S.; Vohra, S.; Pandey, S.; Lal, D.; Negi, R.K.; Lal, R.; Rawat, C.D. Genome analyses of 174 strains of Mycobacterium tuberculosis provide insight into the evolution of drug resistance and reveal potential drug targets. Microb. Genom. 2021, 7, 000542. [Google Scholar] [CrossRef] [PubMed]
- Petrella, S.; Gelus-Ziental, N.; Maudry, A.; Laurans, C.; Boudjelloul, R.; Sougakoff, W. Crystal Structure of the Pyrazinamidase of Mycobacterium tuberculosis: Insights into Natural and Acquired Resistance to Pyrazinamide. PLoS ONE 2011, 6, e15785. [Google Scholar] [CrossRef] [Green Version]
- Scientific, D.; San Carlos, C. The PyMOL molecular graphics system. DeLano WL 2002, 11, 2476–2486. [Google Scholar]
- Schneidman-Duhovny, D.; Inbar, Y.; Nussinov, R.; Wolfson, H.J. PatchDock and SymmDock: Servers for rigid and symmetric docking. Nucleic Acids Res. 2005, 33, W363–W367. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Salomon-Ferrer, R.; Case, D.A.; Walker, R.C. An overview of the Amber biomolecular simulation package. WIREs Comput. Mol. Sci. 2013, 3, 198–210. [Google Scholar] [CrossRef]
- Darden, T.; York, D.; Pedersen, L. Particle mesh Ewald: An N⋅log(N) method for Ewald sums in large systems. J. Chem. Phys. 1993, 98, 10089–10092. [Google Scholar] [CrossRef] [Green Version]
- Ryckaert, J.-P.; Ciccotti, G.; Berendsen, H.J.C. Numerical integration of the cartesian equations of motion of a system with constraints: Molecular dynamics of n-alkanes. J. Comput. Phys. 1977, 23, 327–341. [Google Scholar] [CrossRef] [Green Version]
- Götz, A.W.; Williamson, M.J.; Xu, D.; Poole, D.; Le Grand, S.; Walker, R.C. Routine Microsecond Molecular Dynamics Simulations with AMBER on GPUs. Generalized Born. J. Chem. Theory Comput. 2012, 8, 1542–1555. [Google Scholar] [CrossRef] [PubMed]
- Amadei, A.; Linssen, A.B.M.; Berendsen, H.J.C. Essential dynamics of proteins. Proteins Struct. Funct. Bioinform. 1993, 17, 412–425. [Google Scholar] [CrossRef]
- Hoang, T.X.; Trovato, A.; Seno, F.; Banavar, J.R.; Maritan, A. Geometry and symmetry presculpt the free-energy landscape of proteins. Proc. Natl. Acad. Sci. USA 2004, 101, 7960–7964. [Google Scholar] [CrossRef] [Green Version]
- Miller, I.B.R.; McGee, J.T.D.; Swails, J.M.; Homeyer, N.; Gohlke, H.; Roitberg, A.E. MMPBSA.py: An Efficient Program for End-State Free Energy Calculations. J. Chem. Theory Comput. 2012, 8, 3314–3321. [Google Scholar] [CrossRef]
- Chen, F.; Liu, H.; Sun, H.; Pan, P.; Li, Y.; Li, D.; Hou, T. Assessing the performance of the MM/PBSA and MM/GBSA methods. Capability to predict protein–protein binding free energies and re-rank binding poses generated by protein–protein docking. Phys. Chem. Chem. Phys. 2016, 18, 22129–22139. [Google Scholar] [CrossRef]
- Sun, H.; Duan, L.; Chen, F.; Liu, H.; Wang, Z.; Pan, P.; Zhu, F.; Zhang, J.Z.H.; Hou, T. Assessing the performance of MM/PBSA and MM/GBSA methods. Entropy effects on the performance of end-point binding free energy calculation approaches. Phys. Chem. Chem. Phys. 2018, 20, 14450–14460. [Google Scholar] [CrossRef]
- Xu, L.; Sun, H.; Li, Y.; Wang, J.; Hou, T. Assessing the Performance of MM/PBSA and MM/GBSA Methods. The Impact of Force Fields and Ligand Charge Models. J. Phys. Chem. B 2013, 117, 8408–8421. [Google Scholar] [CrossRef] [PubMed]
- Sun, H.; Li, Y.; Tian, S.; Xu, L.; Hou, T. Assessing the performance of MM/PBSA and MM/GBSA methods. Accuracies of MM/PBSA and MM/GBSA methodologies evaluated by various simulation protocols using PDBbind data set. Phys. Chem. Chem. Phys. 2014, 16, 16719–16729. [Google Scholar] [CrossRef] [PubMed]
- Lee, S.J.; Shin, S.J.; Lee, M.H.; Lee, M.-G.; Kang, T.H.; Park, W.S.; Soh, B.Y.; Park, J.H.; Shin, Y.K.; Kim, H.W. A potential protein adjuvant derived from Mycobacterium tuberculosis Rv0652 enhances dendritic cells-based tumor immunotherapy. PLoS ONE 2014, 9, e104351. [Google Scholar] [CrossRef] [PubMed]
- Junaid, M.; Li, C.-D.; Li, J.; Khan, A.; Ali, S.S.; Jamal, S.B.; Saud, S.; Ali, A.; Wei, D.-Q. Structural insights of catalytic mechanism in mutant pyrazinamidase ofMycobacterium tuberculosis. J. Biomol. Struct. Dyn. 2021, 39, 1–14. [Google Scholar] [CrossRef]
- Ali, A.; Khan, M.T.; Khan, A.; Ali, S.; Chinnasamy, S.; Akhtar, K.; Shafiq, A.; Wei, D.-Q. Pyrazinamide resistance of novel mutations in pncA and their dynamic behavior. RSC Adv. 2020, 10, 35565–35573. [Google Scholar] [CrossRef]
- Nangraj, A.S.; Khan, A.; Umbreen, S.; Sahar, S.; Arshad, M.; Younas, S.; Ahmad, S.; Ali, S.; Ali, S.S.; Ali, L.; et al. Insights Into Mutations Induced Conformational Changes and Rearrangement of Fe2+ Ion in pncA Gene of Mycobacterium tuberculosis to Decipher the Mechanism of Resistance to Pyrazinamide. Front. Mol. Biosci. 2021, 8, 633365. [Google Scholar] [CrossRef]
- Khan, M.T.; Khan, A.; Rehman, A.U.; Wang, Y.; Akhtar, K.; Malik, S.I.; Wei, D.-Q. Structural and free energy landscape of novel mutations in ribosomal protein S1 (rpsA) associated with pyrazinamide resistance. Sci. Rep. 2019, 9, 1–12. [Google Scholar] [CrossRef]
- Suleman, M.; Qamar, M.T.U.; Saleem, S.; Ahmad, S.; Ali, S.S.; Khan, H.; Akbar, F.; Khan, W.; Alblihy, A.; Alrumaihi, F.; et al. Mutational Landscape of Pirin and Elucidation of the Impact of Most Detrimental Missense Variants That Accelerate the Breast Cancer Pathways: A Computational Modelling Study. Front. Mol. Biosci. 2021, 8, 692835. [Google Scholar] [CrossRef]
- Alamri, M.A.; ul Qamar, M.T.; Afzal, O.; Alabbas, A.B.; Riadi, Y.; Alqahtani, S.M. Discovery of anti-MERS-CoV small covalent inhibitors through pharmacophore modeling, covalent docking and molecular dynamics simulation. J. Mol. Liq. 2021, 330, 115699. [Google Scholar] [CrossRef]
- Khalid, R.R.; Qamar, M.T.U.; Maryam, A.; Ashique, A.; Anwar, F.; Geesi, M.H.; Siddiqi, A.R. Comparative Studies of the Dynamics Effects of BAY60-2770 and BAY58-2667 Binding with Human and Bacterial H-NOX Domains. Mol. 2018, 23, 2141. [Google Scholar] [CrossRef] [Green Version]
- Muneer, I.; Tusleem, K.; Abdul Rauf, S.; Hussain, H.M.; Siddiqi, A.R. Discovery of selective inhibitors for cyclic AMP response element-binding protein: A combined ligand and structure-based resources pipeline. Anti-Cancer Drugs 2019, 30, 363–373. [Google Scholar] [CrossRef] [PubMed]
- Alamri, M.A.; Ul Qamar, M.T.; Mirza, M.U.; Alqahtani, S.M.; Froeyen, M.; Chen, L.-L. Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches. J. Pharm. Anal. 2020, 10, 546–559. [Google Scholar] [CrossRef] [PubMed]
- Qamar, M.T.U.; Mirza, M.U.; Song, J.-M.; Rao, M.J.; Zhu, X.; Chen, L.-L. Probing the structural basis of Citrus phytochrome B using computational modelling and molecular dynamics simulation approaches. J. Mol. Liq. 2021, 340, 116895. [Google Scholar] [CrossRef]
Complex | vdW | Elec | ΔPS | SASA | TBE |
---|---|---|---|---|---|
Wild Type | −10.01 | −20.11 | 21.52 | −1.01 | −9.61 |
W68L | −8.22 | −18.52 | 20.15 | −0.98 | −7.57 |
L85P | −6.34 | −19.71 | 22.02 | −2.96 | −6.99 |
T87A | −9.36 | −16.35 | 19.96 | −2.02 | −7.77 |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Alatawi, E.A.; Alshabrmi, F.M. Structural and Dynamic Insights into the W68L, L85P, and T87A Mutations of Mycobacterium tuberculosis Inducing Resistance to Pyrazinamide. Int. J. Environ. Res. Public Health 2022, 19, 1615. https://doi.org/10.3390/ijerph19031615
Alatawi EA, Alshabrmi FM. Structural and Dynamic Insights into the W68L, L85P, and T87A Mutations of Mycobacterium tuberculosis Inducing Resistance to Pyrazinamide. International Journal of Environmental Research and Public Health. 2022; 19(3):1615. https://doi.org/10.3390/ijerph19031615
Chicago/Turabian StyleAlatawi, Eid A., and Fahad M. Alshabrmi. 2022. "Structural and Dynamic Insights into the W68L, L85P, and T87A Mutations of Mycobacterium tuberculosis Inducing Resistance to Pyrazinamide" International Journal of Environmental Research and Public Health 19, no. 3: 1615. https://doi.org/10.3390/ijerph19031615