Computational Approaches for the Inhibition of ESKAPE Pathogens

According to the WHO priority pathogens list, the six nosocomial pathogens that exhibit resistance to several antibiotics are named as ESKAPE, including Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter sp. Since most antibiotics are ineffective against ESKAPE group of microorganisms, it creates selective pressure on the clinical healthcare settings. Hence, it is imperative to design and develop novel therapeutic agents of synthetic and natural origin against these multidrug-resistant (MDR) bacteria. However, the limitations associated with conventional drug discovery pipelines have urged the scientific community to develop reverse pharmacology-based approaches to discover potential therapeutic drug candidates of interest. With the advancement of next generation computational approaches, i.e., computer-aided drug designing (CADD), quantitative structure affinity relationship (QSAR) studies, pharmacophore modelling, and pharmacokinetic profiling using ADMET (Absorption-Digestion-Metabolism-Excretion-Toxicity) predictions, the drug discovery pipelines received quintessential growth in last few years. In silico tools, particularly, molecular docking, MD Simulation, 3D-QSAR, ADMET profiling, etc. are being extensively explored in providing a platform for identifying and developing potential therapeutic agents against several diseases of economic importance. The advanced computational tools and prediction software not only reduced the manpower, time, and selection of drug development processes but also created a favourable atmosphere to design and develop potential drug candidates against chronic microbial infections linked to ESKAPE pathogens. The in silico tools also provide an integrated platform for repurposing of therapeutic drugs toward the mitigation of bacterial infections and biofilms mediated resistance in bacterial pathogens. The present chapter emphasizes the use of advanced computational tools to identify potential drug candidates against ESKAPE pathogens. Besides, CADD-based approaches for FDA approved drugs with potential therapeutic values repurposed towards antibacterial and biofilm inhibition was also critically discussed. This chapter will thus provide new avenues to design and develop potential drug candidates with high throughput therapeutic values in the regulation of bacterial virulence and drug resistance patterns in ESKAPE pathogens in the near future.