Dual transcriptome based reconstruction of Salmonella-human integrated metabolic network to screen potential drug targets

PLoS One. 2022 May 24;17(5):e0268889. doi: 10.1371/journal.pone.0268889. eCollection 2022.

Abstract

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a highly adaptive pathogenic bacteria with a serious public health concern due to its increasing resistance to antibiotics. Therefore, identification of novel drug targets for S. Typhimurium is crucial. Here, we first created a pathogen-host integrated genome-scale metabolic network by combining the metabolic models of human and S. Typhimurium, which we further tailored to the pathogenic state by the integration of dual transcriptome data. The integrated metabolic model enabled simultaneous investigation of metabolic alterations in human cells and S. Typhimurium during infection. Then, we used the tailored pathogen-host integrated genome-scale metabolic network to predict essential genes in the pathogen, which are candidate novel drug targets to inhibit infection. Drug target prioritization procedure was applied to these targets, and pabB was chosen as a putative drug target. It has an essential role in 4-aminobenzoic acid (PABA) synthesis, which is an essential biomolecule for many pathogens. A structure based virtual screening was applied through docking simulations to predict candidate compounds that eliminate S. Typhimurium infection by inhibiting pabB. To our knowledge, this is the first comprehensive study for predicting drug targets and drug like molecules by using pathogen-host integrated genome-scale models, dual RNA-seq data and structure-based virtual screening protocols. This framework will be useful in proposing novel drug targets and drugs for antibiotic-resistant pathogens.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / metabolism
  • Anti-Bacterial Agents / pharmacology
  • Humans
  • Metabolic Networks and Pathways / genetics
  • Salmonella typhimurium*
  • Serogroup
  • Transcriptome*

Substances

  • Anti-Bacterial Agents

Grants and funding

This work was supported by TUBITAK, The Scientific and Technological Research Council of Turkey (Project Code: 316S005) and by PSF, The Pakistan Science Foundation [Project Code: PSF-TUBITAK/S-HEJ (04)]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.