A computational perspective on the dynamic behaviour of recurrent drug resistance mutations in the pncA gene from <i>Mycobacterium tuberculosis</i>

Khan, Taimoor; Khan, Abbas; Ali, Syed Shujait; Ali, Shahid; Wei, Dong‐Qing

doi:10.1039/d0ra09326b

Cited by 9 publications

(7 citation statements)

References 48 publications

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“…However, these studies are computationally intensive and are difficult to scale for studying hundreds of mutations. A recent MD study on a subset of mutations found within our dataset analysed seven pncA nsSNPs (F94L, F94S, K96N, K96R, G97C, G97D, and G97S) showed that these destabilising mutations altered the binding pocket, allowing increased PZA flexibility ( Khan et al, 2021 ). All seven mutations were associated with PZA resistance and also showed destabilising effects in our study.…”

Section: Discussionmentioning

confidence: 93%

“…The motivation for investigating the missense mutations within the protein coding region only of the pncA gene was to enable understanding of the phenotypic mutational effects in relation to PZA resistance development. While the exact molecular mechanisms of PZA resistance are yet to be fully elucidated, the binding pocket of PZA and its key interactions are well known and characterised ( Petrella et al, 2011 ; Ali et al, 2020 ; Sheik Amamuddy et al, 2020 ; Khan et al, 2021 ). This knowledge was used to guide the molecular docking of PZA to generate the pncA-PZA complex in the absence of an experimentally solved structure of the bound complex in Mtb.…”

Section: Discussionmentioning

confidence: 99%

“…While docking generates a variety of ligand conformations (poses), choosing the “best” pose is based on considerations around key molecular interactions formed by the ligand, interaction energy of the docked complex and subject expertise. Using these guides, docking pose 1 was chosen due to its molecular interactions with known key residues and close alignment with previously published studies ( Karmakar et al, 2018 ; Ali et al, 2020 ; Khan et al, 2021 ). In addition, we analysed the top two docking poses using the mCSM pipeline ( Supplementary Figure 3 ).…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Structural and Genomic Insights Into Pyrazinamide Resistance in Mycobacterium tuberculosis Underlie Differences Between Ancient and Modern Lineages

Tunstall

Phelan

Eccleston

et al. 2021

Front. Mol. Biosci.

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Resistance to drugs used to treat tuberculosis disease (TB) continues to remain a public health burden, with missense point mutations in the underlying Mycobacterium tuberculosis bacteria described for nearly all anti-TB drugs. The post-genomics era along with advances in computational and structural biology provide opportunities to understand the interrelationships between the genetic basis and the structural consequences of M. tuberculosis mutations linked to drug resistance. Pyrazinamide (PZA) is a crucial first line antibiotic currently used in TB treatment regimens. The mutational promiscuity exhibited by the pncA gene (target for PZA) necessitates computational approaches to investigate the genetic and structural basis for PZA resistance development. We analysed 424 missense point mutations linked to PZA resistance derived from ∼35K M. tuberculosis clinical isolates sourced globally, which comprised the four main M. tuberculosis lineages (Lineage 1–4). Mutations were annotated to reflect their association with PZA resistance. Genomic measures (minor allele frequency and odds ratio), structural features (surface area, residue depth and hydrophobicity) and biophysical effects (change in stability and ligand affinity) of point mutations on pncA protein stability and ligand affinity were assessed. Missense point mutations within pncA were distributed throughout the gene, with the majority (>80%) of mutations with a destabilising effect on protomer stability and on ligand affinity. Active site residues involved in PZA binding were associated with multiple point mutations highlighting mutational diversity due to selection pressures at these functionally important sites. There were weak associations between genomic measures and biophysical effect of mutations. However, mutations associated with PZA resistance showed statistically significant differences between structural features (surface area and residue depth), but not hydrophobicity score for mutational sites. Most interestingly M. tuberculosis lineage 1 (ancient lineage) exhibited a distinct protein stability profile for mutations associated with PZA resistance, compared to modern lineages.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Structural and Genomic Insights Into Pyrazinamide Resistance in Mycobacterium tuberculosis Underlie Differences Between Ancient and Modern Lineages

Tunstall

Phelan

Eccleston

et al. 2021

Front. Mol. Biosci.

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“…However, in the middle of the last century, drug-resistant forms of TB were identified. A rapid spread of antibiotic-resistant strains of Mtb was observed, on which standard chemotherapy has practically no effect [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. In the future, worsening of the situation should be expected.…”

Section: Introductionmentioning

confidence: 99%

Analogues of Pyrimidine Nucleosides as Mycobacteria Growth Inhibitors

et al. 2022

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Tuberculosis (TB) is the oldest human infection disease. Mortality from TB significantly decreased in the 20th century, because of vaccination and the widespread use of antibiotics. However, about a third of the world’s population is currently infected with Mycobacterium tuberculosis (Mtb) and the death rate from TB is about 1.4–2 million people per year. In the second half of the 20th century, new extensively multidrug-resistant strains of Mtb were identified, which are steadily increasing among TB patients. Therefore, there is an urgent need to develop new anti-TB drugs, which remains one of the priorities of pharmacology and medicinal chemistry. The antimycobacterial activity of nucleoside derivatives and analogues was revealed not so long ago, and a lot of studies on their antibacterial properties have been published. Despite the fact that there are no clinically used drugs based on nucleoside analogues, some progress has been made in this area. This review summarizes current research in the field of the design and study of inhibitors of mycobacteria, primarily Mtb.

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“…Computational methods are of great interest in exploring biological mechanisms and designing therapeutics against the emerging pathogens (21,22). This also involves the application of computational vaccinology approaches to design vaccine therapeutics.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Whole Proteome of Achromobacter xylosoxidans to Identify Vaccine Targets for mRNA and Peptides-Based Vaccine Designing Against the Emerging Respiratory and Lung Cancer-Causing Bacteria

Khan

Abdullah

Toor³

et al. 2022

Front. Med.

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Achromobacter xylosoxidans is a rod-shaped Gram-negative bacterium linked with causing several infections which mostly includes hematological malignancies. It has been recently reported to be associated with the development and progression of lung cancer and is an emerging respiratory disease-causing bacterium. The treatment of individuals infected with A. xylosoxidans bacteremia is difficult due to the fact that this pathogen has both intrinsic and acquired resistance mechanisms, typically resulting in a phenotype of multidrug resistance (MDR). Efforts are needed to design effective therapeutic strategies to curtail the emergence of this bacterium. Computational vaccine designing has proven its effectiveness, specificity, safety, and stability compared to conventional approaches of vaccine development. Therefore, the whole proteome of A. xylosoxidans was screened for the characterization of potential vaccine targets through subtractive proteomics pipeline for therapeutics design. Annotation of the whole proteome confirmed the three immunogenic vaccine targets, such as (E3HHR6), (E3HH04), and (E3HWA2), which were used to map the putative immune epitopes. The shortlisted epitopes, specific against Cytotoxic T Lymphocytes, Helper T-cell Lymphocytes, and linear B-Cell, were used to design the mRNA and multi-epitopes vaccine (MEVC). Initial validations confirmed the antigenic and non-allergenic properties of these constructs, followed by docking with the immune receptor, TLR-5, which resulted in robust interactions. The interaction pattern that followed in the docking complex included formation of 5 hydrogen bonds, 2 salt bridges, and 165 non-bonded contacts. This stronger binding affinity was also assessed through using the mmGBSA approach, showing a total of free binding energy of −34.64 kcal/mol. Further validations based on in silico cloning revealed a CAI score of 0.98 and an optimal percentage of GC contents (54.4%) indicated a putatively higher expression of the vaccine construct in Escherichia coli. Moreover, immune simulation revealed strong antibodies production upon the injection of the designed MEVC that resulted in the highest peaks of IgM+ IgG production (>3,500) between 10 and 15 days. In conclusion the current study provide basis for vaccine designing against the emerging A. xylosoxidans, which demands further experimental studies for in vitro and in vivo validations.

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A computational perspective on the dynamic behaviour of recurrent drug resistance mutations in the pncA gene from Mycobacterium tuberculosis

Abstract: Tuberculosis is still one of the top 10 causes of death worldwide, particularly with the emergence of multidrug-resistant tuberculosis.

Cited by 9 publications

References 48 publications

Structural and Genomic Insights Into Pyrazinamide Resistance in Mycobacterium tuberculosis Underlie Differences Between Ancient and Modern Lineages

Structural and Genomic Insights Into Pyrazinamide Resistance in Mycobacterium tuberculosis Underlie Differences Between Ancient and Modern Lineages

Analogues of Pyrimidine Nucleosides as Mycobacteria Growth Inhibitors

Evaluation of the Whole Proteome of Achromobacter xylosoxidans to Identify Vaccine Targets for mRNA and Peptides-Based Vaccine Designing Against the Emerging Respiratory and Lung Cancer-Causing Bacteria

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