An integrated proteo-transcriptomics approach reveals novel drug targets against multidrug resistant Escherichia coli

Abstract

Infections due to multidrug-resistant (MDR) Escherichia coli are associated with severe morbidity and mortality, worldwide. Microbial drug resistance is a complex phenomenon which is conditioned by an interplay of several genomic, transcriptomic and proteomic factors. Here, we have conducted an integrated transcriptomics and proteomics analysis of MDR E. coli to identify genes which are differentially expressed at both mRNA and protein levels. Using RNA-Seq and SWATH-LC MS/MS it was discerned that 763 genes/proteins exhibited differential expression. Of these, 52 genes showed concordance in differential expression at both mRNA and protein levels with 41 genes exhibiting overexpression and 11 genes exhibiting under expression. Bioinformatic analysis using GO-terms, COG and KEGG functional annotations revealed that the concordantly overexpressed genes of MDR E. coli were involved primarily in biosynthesis of secondary metabolites, aminoacyl-tRNAs and ribosomes. Protein–protein interaction (PPI) network analysis of the concordantly overexpressed genes revealed 81 PPI networks and 10 hub proteins. The hub proteins (rpsI, aspS, valS, lysS, accC, topA, rpmG, rpsR, lysU, and spmB) were found to be involved in aminoacylation of tRNA and lysyl-tRNA and, translation. Further, it was discerned that three hub proteins - smpB, rpsR, and topA were non homologous to human proteins and were involved in several biological pathways directly and/or indirectly related to antibiotic stress. Also, absence of homology ensures a little cross-reactivity of their inhibitors/drugs with human proteins and undesirable side effects. Thus, these proteins might be explored as novel drug targets against both drug-resistant and -sensitive populations of E. coli.