Prospects of indole derivatives as methyl transfer inhibitors: amr managers

Abstract

It is prudent that new antibiotics be urgently developed as to manage WHO listed critical and high priority nine multi-drug resistant (MDR) pathogens posing unprecedented medical crisis. Simultaneously, multiple essential proteins have to be targeted to prevent easy resistance development. Whole genome sequences of these pathogens were aligned exploiting DNA alignment potential of MAUVE software to identify putative common lead target proteins in all nine pathogens. S-adenosyl methionine (SAM), a critical metabolite in several biochemical reactions, biosynthesizing metK gene was taken as the lead target and the gene essentiality analysis using COBRA tool revealed that SAM is a critical metabolite. Furthermore, gene essentiality of corrin methylation steps revealed cobA gene as essential. Hence, from the library of 715 indole derivatives, chosen based on kinase inhibition potential of some indoles, around 102 were pursued based on ADME/T scores. Among these, the 58 higher binding derivatives against N. gonorrhoea MetK were further expanded to MetK proteins of all nine pathogens and 9 derivatives exhibited higher binding energy. These, 58 upon docking to other SAM utilizing enzymes, CobA, CysG, Dam, TrmD and cis regulatory RNA SAM-I riboswitch, 8 derivatives had higher binding energy and six had multi-target including MetK in all pathogens. Further, docking with human metK homologue showed 1-Methyl-3,4-bis(3indolyl) maleimide as the only drug candidate with minimal effects on human but inhibitory effects on all studied targets. The molecule could be developed to treat infections caused by N. gonorrhoea, A. baumanii, C. coli, K. pneumoniae, E. faecium, H. pylori, P. aeruginosa, S. aureus and S. typhii. Key words: In silico virtual screening, WHO priority pathogens, drug resistance, putative antimicrobials, Indole