In silico structural and mechanical insights into bedaquiline resistance associated with high-grade non-synonymous mutations in atpE, mmpR5, and pepQ.

Clinical resistance against bedaquiline (BDQ) remains intractable to anti-tuberculosis therapies since its introduction to the market over a decade ago. Herein, we investigated the structural and mechanical aspects of BDQ resistance in AtpE, MmpR5, and PepQ. The known target-specific resistant single non-synonymous mutations were refined to high-grade candidates. Thus, 7 (AtpE), 5 (MmpR5), and 1 (PepQ) single nucleotide polymorphisms (SNPs) and one insertion frameshift mutation in MmpR5 were recreated at the molecular level, and these phenotypic models were then directed to stringent dynamics to define time-scaled changes. The AtpE variants destabilized the structure; mainly, L59V, E61D, and I66M were detrimental to the complex fitness, while L74V and L114P boosted the BDQ binding to MmpR5. The first three and last two alterations gave rise to loss- and gain-of-function to AtpE and MmpR5, respectively. Hence, these five mutants are functionally relevant and therapeutically targetable hotspots of BDQ resistance. There were no noticeable changes in PepQ data analysis. The present study revealed that MmpR5 mutations confer BDQ resistance, whereas AtpE and PepQ SNPs display low susceptibility. These results were tallied with the published findings, which testified to the pursued method's reliability and accuracy. We hope these data and inferences could be helpful for the futuristic design of novel TB drugs.Communicated by Ramaswamy H. Sarma.

Designing multi-epitope based peptide vaccine targeting spike protein SARS-CoV-2 B1.1.529 (Omicron) variant using computational approaches.

Millions of lives have been infected since the SARS-CoV-2 outbreak in 2019. The high human-to-human transmission rate has warranted a need for a vaccine to protect people. Although some vaccines are in use, due to the high mutation rate in the SARS-CoV-2 multiple variants, the current vaccines may not be sufficient to immunize people against new variant threats. One of the emerging concern variants is B1.1.529 (Omicron), which carries ~ 30 mutations in the Spike protein (S) of SARS-CoV-2 and is predicted to evade antibody recognition even from vaccinated people. We used a structure-based approach and an epitope prediction server to develop a Multi-Epitope based Subunit Vaccine (MESV) involving SARS-CoV-2 B1.1.529 variant spike glycoprotein. The predicted epitope with better antigenicity and non-toxicity was used for designing and predicting vaccine construct features and structure models. In addition, the MESV construct In silico cloning in the pET28a expression vector predicted the construct to be highly translational. The proposed MESV vaccine construct was also subjected to immune simulation prediction and was found to be highly antigenic and elicit a cell-mediated immune response. Therefore, the proposed MESV in the present study has the potential to be evaluated further for vaccine production against the newly identified B1.1.529 (Omicron) variant of concern. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-02027-6.