Prioritising Uropathogenic Escherichia coli Drug Targets: Network Analysis and Inhibitor Identification

Urinary tract infections (UTIs) are among the most prevalent infections globally. Uropathogenic Escherichia coli (UPEC) is the most frequent infectious agent that causes UTIs. Antibiotic treatment of UTIs is becoming problematic due to the development of high rates of "antimicrobial resistance" (AMR). Therefore, newer and more effective antibiotics need to be developed. In this study, we employed an in-silico approach, wherein a non-redundant analysis was carried out on the entire proteome of UPEC strain CFT073. We aimed to identify potential drug targets critical for UPEC survival with no similarity to human hosts.

Various computational tools were adopted to identify novel drug targets and inhibitors. Firstly, sequence retrieval was done from NCBI. Further, the CD-HIT tool removed redundant "human-specific" sequences from the UPEC proteome. After that, "metabolic pathway analysis, protein-protein interaction network analysis, and subcellular location analysis" were performed. From in-silico screening, we found MurF to be the best potential drug target. According to our knowledge, this is the first report to screen a library of 1615 chemicals licensed drugs against MurF. Molecular docking of 1615 FDA-approved against MurF was carried out to identify top-ranked drugs based on scoring functions and interactions with active sites. Molecular docking and simulation analysis confirmed telithromycin as one of the best-repurposed drugs.

The current study provides an example of the repurposing of FDA-approved drugs that could potentially treat UTIs. Further "in vitro" and "in vivo" studies are needed to confirm the efficacy of telithromycin before its clinical use.