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Review
. 2019 Apr 10;20(7):1781.
doi: 10.3390/ijms20071781.

Two Component Regulatory Systems and Antibiotic Resistance in Gram-Negative Pathogens

Anjali Y Bhagirath  1 , Yanqi Li  2 , Rakesh Patidar  3 , Katherine Yerex  4 , Xiaoxue Ma  5 , Ayush Kumar  6 , Kangmin Duan  7   8
Affiliations
Review

Two Component Regulatory Systems and Antibiotic Resistance in Gram-Negative Pathogens

Anjali Y Bhagirath et al. Int J Mol Sci. .

Abstract

Gram-negative pathogens such as Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa are the leading cause of nosocomial infections throughout the world. One commonality shared among these pathogens is their ubiquitous presence, robust host-colonization and most importantly, resistance to antibiotics. A significant number of two-component systems (TCSs) exist in these pathogens, which are involved in regulation of gene expression in response to environmental signals such as antibiotic exposure. While the development of antimicrobial resistance is a complex phenomenon, it has been shown that TCSs are involved in sensing antibiotics and regulating genes associated with antibiotic resistance. In this review, we aim to interpret current knowledge about the signaling mechanisms of TCSs in these three pathogenic bacteria. We further attempt to answer questions about the role of TCSs in antimicrobial resistance. We will also briefly discuss how specific two-component systems present in K. pneumoniae, A. baumannii, and P. aeruginosa may serve as potential therapeutic targets.

Keywords: antimicrobial resistance; biofilms; two-component regulatory proteins.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Key resistance mechanisms in gram-negative pathogenic bacteria.
Figure 2
Figure 2
Schematic diagram of the functions and domains of sensor kinase and response regulator proteins in TCSs and HHK-mediated phosphorelays. (A) Representation of the classical TCS and phosphorelay signaling systems. (B) Structure of the complex between the entire cytoplasmic portion of Thermotoga maritima class I histidine kinase (magenta) and its cognate, response regulator (green) (PDB entry code 3 DGE) [91].
Figure 3
Figure 3
Phylogenetic analysis of the HKs of P. aeruginosa. Known HKs were aligned followed by phylogenetic analysis at Phylogeny.fr [93,94].
Figure 4
Figure 4
Schematic diagram of the direct protein-protein interaction mediated signaling using the PA1611-RetS interaction model as an example [96]. (A) Canonical TC Sensor GacS phosphorylates its response regulator GacA to regulate virulence in P. aeruginosa; however, under yet unknown environmental signals, HHK PA1611 is activated and binds to HHK RetS. Under such conditions, GacS is again free to phosphorylate its cognate response regulator and mediate downstream signaling. (B) A docked complex for homology models for PA1611 and RetS showing predicted interacting surfaces.
Figure 5
Figure 5
The known roles of PmrAB, GacSA, AdeRS, and BaeSR, two-component regulatory systems in antimicrobial resistance.
See this image and copyright information in PMC

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