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, 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.