Abstract
BackgroundIt is prudent that novel classes of antibiotics be urgently developed to manage the WHO prioritized multi-drug resistant (MDR) pathogens posing an unprecedented medical crisis. Simultaneously, multiple essential proteins have to be targeted to prevent easy resistance development.MethodsAn integration of structure-based virtual screening and ligand-based virtual screening was employed to explore the antimicrobial properties of indole derivatives from a compound database.ResultsWhole-genome sequences of the target pathogens were aligned exploiting DNA alignment potential of MAUVE to identify putative common lead target proteins. S-adenosyl methionine (SAM) biosynthesizing MetK was taken as the lead target and various literature searches revealed that SAM is a critical metabolite. Furthermore, SAM utilizing CobA involved in the B12 biosynthesis pathway, Dam in the regulation of replication and protein expression, and TrmD in methylation of tRNA were also taken as drug targets. The ligand library of 715 indole derivatives chosen based on kinase inhibition potential of indoles was created from which 102 were pursued based on ADME/T scores. Among these, 5 potential inhibitors of MetK in N. gonorrhoeae were further expanded to molecular docking studies in MetK proteins of all nine pathogens among which 3 derivatives exhibited inhibition potential. These 3 upon docking in other SAM utilizing enzymes, CobA, Dam, and TrmD gave 2 potential compounds with multiple targets. Further, docking with human MetK homolog also showed probable inhibitory effects however SAM requirements can be replenished from external sources since SAM transporters are present in humans.ConclusionsWe believe these molecules 3-[(4-hydroxyphenyl)methyl]-6-(1H-indol-3-ylmethyl)piperazine-2,5-dione (ZINC04899565) and 1-[(3S)-3-[5-(1H-indol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyrrolidin-1-yl]ethanone (ZINC49171024) could be a starting point to help develop broad-spectrum antibiotics against infections caused by N. gonorrhoeae, A. baumannii, C. coli, K. pneumoniae, E. faecium, H. pylori, P. aeruginosa, S. aureus and S. typhi.
Highlights
It is prudent that novel classes of antibiotics be urgently developed to manage the World Health Organization (WHO) prioritized multi-drug resistant (MDR) pathogens posing an unprecedented medical crisis
The emergence of antibiotic-resistant strains among these pathogens appears to be inevitable as selective pressure for survival [1]
The most alarming is the prevalence of resistance even in the last resort antibiotic colistin [2] that has added a serious challenge to the current antibiotic crisis
Summary
It is prudent that novel classes of antibiotics be urgently developed to manage the WHO prioritized multi-drug resistant (MDR) pathogens posing an unprecedented medical crisis. Multiple essential proteins have to be targeted to prevent easy resistance development. The finding and development of antibiotics was a milestone in medical sciences that prevented fatality from simple infections. The rapid increase in drug resistance among pathogens and the excessive time and cost parameters required to develop a drug demand a robust and faster method of drug discovery. This is where computational strategies come into play, efficiently assisting drug discovery and development with the available in vitro techniques [4]
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