Comparative genomics and e-pharmacophore search to identify novel therapeutic targets in the druggable genome of MDR Providencia stuartii.

OBJECTIVES/

BACKGROUND

Providencia species of the Enterobacteriaceae family is a frequent cause of hospitalised infections, primarily urinary tract infections. It has a major influence on patient morbidity, mortality, and therapy. They can cause pneumonia, meningitis, endocarditis, wound and bloodstream infections, thereby requiring serious attention for novel therapeutics identification at the preliminary stages of disease.

METHODS

The AST (antimicrobial susceptibility test) of P. stuartii strains (n = 91) was followed by whole-genome sequencing using Oxford Nanopore MinION technology, comparative genomics (n = 19), resistome, and pharmacogenomics analyses. Pharmacokinetics and physicochemical characterisation of putative druggable targets and novel inhibitors were also evaluated.

RESULTS

The reported genome is ∼4.43 Mb long, and the resistome has 30 different AMR genes. The pangenome revealed that it is open ('b' = 0.2314), and the core genome (n = 2611) revealed three potential targets that were screened against a peptidomimetic (n = 30,695) and a synthetic Isosteviol library (n = 37) for ensuing docking analyses. The top hit for each target was rendered to an MD (molecular dynamics) simulation. The stability of the apo- and complexes showed good indicators; RMSD (root mean square deviation) (proteins <5 Å, ligands <2 Å). However, an initial fluctuation followed by stability for RMSF (root mean square fluctuation) (< 15 Å), Rg (radius of gyration), and ∆E (binding free energy) was observed for the remaining 100 ns. The ∆E surged negatively, whereas the proportion of ∆G (Gibbs free energy), electrostatic, and Van der Waals contributions was similar.

CONCLUSION

All three complexes, F1510072_ATP (multidrug export ATP-binding permease), ZC440183_PchR (regulatory protein), and F7240201_MT (murein transglycosylase), represent potential therapeutic targets. Such studies could robustly identify targets in the druggable genome of P. stuartii and other microbial pathogens.