In Silico Prediction and Prioritization of Novel Selective Antimicrobial Drug Targets in Escherichia coli

Abstract

Novel antimicrobials interfering with pathogen-specific targets can minimize the risk of perturbations of the gut microbiota (dysbiosis) during therapy. We employed an in silico approach to identify essential proteins in Escherichia coli that are either absent or have low sequence identity in seven beneficial taxa of the gut microbiota: Faecalibacterium, Prevotella, Ruminococcus,&nbsp;Bacteroides, Lactobacillus, Lachnospiraceae and Bifidobacterium. We identified 36 essential proteins that are present in hyper-virulent E. coli ST131 and have low similarity (bitscore < 50 or identity < 30% and alignment length < 25%) to proteins in mammalian hosts and beneficial taxa. Of these, 35 are also present in Klebsiella pneumoniae. None of the proteins are targets of clinically used antibiotics, and 3D structure is available for 23 of them. Four proteins (LptD, LptE, LolB and BamD) are easily accessible as drug targets due to their location in the outer membrane, especially LptD, which contains extracellular domains. Our results indicate that it may be possible to selectively interfere with essential biological processes in Enterobacteriaceae that are absent or mediated by unrelated proteins in beneficial taxa residing in the gut. The identified targets can be used to discover antimicrobial drugs effective against these opportunistic pathogens with a decreased risk of causing dysbiosis.

Keywords: Escherichia coli; antimicrobial targets; in silico; microbiota.

Figure 1

Flow diagram showing the different steps of the selection procedure used to identify novel selective antimicrobial drug targets against E. coli.

Figure 2

Function and SCL of the identified protein targets. The identified targets are drawn in pink, with surrounding proteins in gray. The proteins drawn are part of various cellular processes, including cell cycle (ZipA, FtsB, FtsL, FtsQ, MukB, MukE and MukF), cell shape (MreD), transport (CydX), outer membrane processes (BamD, SecE, LolA, LolB, LptA, LptD and LptE) and DNA replication (DnaT, PriB and HolD). Other inner membrane proteins are WzyE, YciS, YrfF and SafA, and cytoplasmic proteins are FabA, IraM, TusE, YgfZ and YcaR. Proteins without a determined SCL are not shown: HemD, TrpL, HigA, HipB, PheM, YdfO, YdhL and YqeL.