Insight into the PZA resistance whole genome of Mycobacterium tuberculosis isolates from Khyber Pakhtunkhwa, Pakistan

Abstract

Background Tuberculosis (TB) is a global public health issue, getting worse due to emergence of resistance. Pyrazinamide (PZA) is first-line antimicrobial drugs used against non-replicated Mycobacterium tuberculosis (MTB). Data is scarce about whole genome sequencing of PZA resistance (PZA-R) in Khyber Pakhtunkhwa (KP) province of high burden country, Pakistan. In the current study we aimed to find the most common mutations in PZA-R MTB isolates in association with other candidate genes in a whole genome sequence (WGS). Samples were collected from TB suspects and drug susceptibility testing (DST) was performed according according to the WHO standards. The resistant samples were subjected for whole genome sequencing (WGS). The sequence data was through MTBseq and Total Genotyping Solution for Mycobacterium tuberculosis (TGS-TB). Metabolic model was analyzed, using RAST server. Results Among the three whole genome sequences, (NCBI BioProject Accession: PRJNA629298, PRJNA629388) 1997, 1162, and 2053 mutations including indel, was detected. Diverse variability has been detected in the membrane proteins PE and PPE, modulating the host immune response. Nine mutations in coding and promotor region have been detected in pncA with one novel (T-4C) variants. Mutations in the other drug candidate genes, KatG, rpoB have also been detected. Conclusion The metabolic model shows a distinct property. Diversity of variants has been detected in majority of MTB essential genes, functions from cell growth to cell signaling. The current study provides useful information, associated with geographic specific strains for biomarkers development and better management of drug resistance isolates.

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

“…This leads to strong side effects on the patients and lower survival chances ( Akhmetova et al, 2015 ; Khan et al, 2018d ). Mitchison (1985) , Miotto et al (2014 , 2017) , Shi et al (2014) , Junaid et al (2018) , and Khan et al (2020f) . Since 1972, PZA was used as an active drug against the Mtb by targeting panD gene and had played key role in clearing persistent Mtb.…”

“…It has been noticed that binding of PZA to the PZase enzyme altered protein’s conformation, which is valuable data-keeping their importance in the quest of novel drug design. Likewise, MD simulations made it possible to study conformational variations in the three-dimensional structure of proteins that may arise following mutation(s) in the sequence ( Khan et al, 2019c , 2020b , f ). Thus MD simulations decrease time, costs and resources by reducing the number of cases for which experimental evaluation is required ( Dolatkhah et al, 2017 ).…”

Repurposing fusion inhibitor peptide against SARS‐CoV‐2

“…It can minimize time and expenses with contrast to de-novo drug discovery. [24][25][26] Since the emergence of COVID-19, numerous clinical trial have been carried out for developing vaccines and repurposing the approved drugs counting chloroquine, arbidol, camostat, remdesivir, ribavirin, and lopinavir/ritonavir against SARS CoV-2. 27,28 Nonetheless, the greater part of these drugs have made a limited commitment to controlling the pandemic.…”

Direct Synthesis of Diamides from Dicarboxylic Acids with Amines Using Nb2O5 as a Lewis Acid Catalyst and Molecular Docking Studies as Anticancer Agents

“…The root-mean-square fluctuation (RMSF) 38 helps to understand the region of protein that is being fluctuated during the MD simulation, and the flexibility of per residue is computed to get better acumen on the extent to which the binding of ligand affects the protein flexibility.…”