Pangenome analytics reveal two-component systems as conserved targets in ESKAPEE pathogens

Akanksha Rajput, Yara Seif, Kumari Sonal Choudhary, Christopher Dalldorf, Saugat Poudel, Jonathan M. Monk, Bernhard O. Palsson*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

The two-component system (TCS) helps bacteria sense and respond to environmental stimuli through histidine kinases and response regulators. TCSs are the largest family of multistep signal transduction processes, and they are involved in many important cellular processes such as antibiotic resistance, pathogenicity, quorum sensing, osmotic stress, and biofilms. Here, we perform the first comprehensive study to highlight the role of TCSs as potential drug targets against ESKAPEE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp., and Escherichia coli) pathogens through annotation, mapping, pangenomic status, gene orientation, and sequence variation analysis. The distribution of the TCSs is group specific with regard to Gram-positive and Gram-negative bacteria, except for KdpDE. The TCSs among ESKAPEE pathogens form closed pangenomes, except for Pseudomonas aeruginosa. Furthermore, their conserved nature due to closed pangenomes might make them good drug targets. Fitness score analysis suggests that any mutation in some TCSs such as BaeSR, ArcBA, EvgSA, and AtoSC, etc., might be lethal to the cell. Taken together, the results of this pangenomic assessment of TCSs reveal a range of strategies deployed by the ESKAPEE pathogens to manifest pathogenicity and antibiotic resistance. This study further suggests that the conserved features of TCSs might make them an attractive group of potential targets with which to address antibiotic resistance. IMPORTANCE The ESKAPEE pathogens are the leading cause of health care-associated infections worldwide. Two-component systems (TCSs) can be used as effective targets against pathogenic bacteria since they are ubiquitous and manage various vital functions such as antibiotic resistance, virulence, biofilms, quorum sensing, and pH balance, among others. This study provides a comprehensive overview of the pangenomic status of the TCSs among ESKAPEE pathogens. The annotation and pangenomic analysis of TCSs show that they are significantly distributed and conserved among the pathogens, as most of them form closed pangenomes. Furthermore, our analysis also reveals that the removal of the TCSs significantly affects the fitness of the cell. Hence, they may be used as promising drug targets against bacteria.

Original languageEnglish
Article numbere00981-20
JournalmSystems
Volume6
Issue number1
ISSN2379-5077
DOIs
Publication statusPublished - 26 Jan 2021

Bibliographical note

Funding Information:
We thank Marc Abrams for reviewing the manuscript and providing constructive suggestions. This work was supported by NIH grant U01 AI124316 and Novo Nordisk Foundation grant NNF10CC1016517. A.R. and B.O.P. designed research. A.R., Y.S., and K.S.C. performed research. A.R., Y.S., K.S.C., C.D., S.P., and J.M. performed analyses. A.R. and Y.S. wrote the manuscript. All the authors have read and approved the manuscript. We declare no competing interests.

Publisher Copyright:
Copyright © 2021 Rajput et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords

  • Antibiotic resistance
  • ESKAPEE pathogens
  • Genomic architecture
  • Pangenomic analysis
  • Two-component systems

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