Analysis of stress response in multiple bacterial pathogens using a network biology approach

Abstract

Stress response in bacterial pathogens promotes adaptation, virulence and antibiotic resistance. In this study, a network approach is applied to identify the common central mediators of stress response in five emerging opportunistic pathogens; Enterococcus faecium Aus0004, Staphylococcus aureus subsp. aureus USA300, Klebsiella pneumoniae MGH 78,578, Pseudomonas aeruginosa PAO1, and Mycobacterium tuberculosis H37Rv. A Protein-protein interaction network (PPIN) was constructed for each stressor using Cytoscape3.7.1 from the differentially expressed genes obtained from Gene expression omnibus datasets. A merged PPIN was constructed for each bacterium. Hub-bottlenecks in each network were the central stress response proteins and common pathways enriched in stress response were identified using KOBAS3.0. 31 hub-bottlenecks were common to each individual stress response, merged networks in all five pathogens and an independent cross stress (CS) response dataset of Escherichia coli. The 31 central nodes are in the RpoS mediated general stress regulon and also regulated by other stress response systems. Analysis of the 20 common metabolic pathways modulating stress response in all five bacteria showed that carbon metabolism pathway had the highest crosstalk with other pathways like amino acid biosynthesis and purine metabolism pathways. The central proteins identified can serve as targets for novel wide-spectrum antibiotics to overcome multidrug resistance.

Keywords: Bacterial pathogen; Centrality; Differentially expressed genes; Protein protein interaction network; Stress response.

Fig. 1

Overlapping central proteins modulating stress response in five pathogenic bacteria: The orange ellipse represents central proteins in EF-PPIN, green ellipse represents central proteins in SA-PPIN, blue ellipse represents central proteins in KP-PPIN, yellow ellipse represents central proteins in PA-PPIN, pink ellipse represents central proteins in MT-PPIN.

Fig. 2

Overlapping enriched pathways modulating stress response in five pathogenic bacteria: The orange ellipse represents the pathways enriched in EF-PPIN, green ellipse represents pathways enriched in SA-PPIN, blue ellipse represents pathways enriched in KP-PPIN, yellow ellipse represents pathways enriched in PA-PPIN, pink ellipse represents central proteins in MT-PPIN.

Fig. 3

Involvement of the 31 central proteins identified in various stress response pathways.

Fig. 4

Crosstalk between the common enriched pathways in the 5 bacterial stress response networks (a) SA-PPIN, (b) EF-PPIN, (c) MT-PPIN, (d) PA-PPIN and (e) KP-PPIN. The clusters represent the proteins in each numbered pathway, while edges show the interactions between the proteins in different pathways. The central nodes are depicted to be bigger than the other nodes. The pathway clusters are numbered in all the networks as follows: (1) 2-Oxocarboxylic acid metabolism; (2) Alanine, aspartate and glutamate metabolism; (3) Amino sugar and nucleotide sugar metabolism; (4) Arginine Biosynthesis; (5) Biosynthesis of amino acids; (6) Carbon metabolism; (7) Citrate cycle (TCA cycle); (8) Cysteine and methionine metabolism; (9) Glycine, serine and threonine metabolism; (10) Glyoxylate and dicarboxylate metabolism; 11. Nicotinate and nicotinamide metabolism; 12. One carbon by folate; 13. Oxidative Phosphorylation; 14. Pentose phosphate pathway; 15. Purine metabolism; 16. Pyrimidine metabolism; 17. Pyruvate metabolism; 18. Ribosome; 19. Starch and sucrose metabolism.