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

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.

Inactivation of Glutamine Synthetase-Coding Gene glnA Increases Susceptibility to Quinolones Through Increasing Outer Membrane Protein F in Salmonella enterica Serovar Typhi

“…In E. coli previous findings indicate that ompF is under the control of NtrBC two-component system encoded by glnL and glnG, as observed in microarray assays (Zimmer et al, 2000). In enterobacteria, these genes are found downstream of glnA and are involved in the stress response of enteric bacteria to nitrogen-limited growth (Bhagirath et al, 2019) (Supplementary Figure 2). The deletion of glnA increases the expression of glnL and glnG, 12-and 8-times respectively, compared to S. Typhi WT (Figure 5), indicating that glnA negatively regulates expression of glnL and glnG through maintaining steady concentrations of glutamine.…”

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

“…The histidine kinase (HK) and response regulator (RR) are two important components of TCSs (Ibrahim, Puthiyaveetil, and Allen 2016) . HK is a transmembrane protein which senses external signals (Bhagirath et al 2019;West and Stock 2001) . Upon sensing the environmental stimuli, the conserved histidine residue gets autophosphorylated by receiving gamma-phosphate from ATP.…”

“…TCSs are involved in antibiotic resistance, virulence, quorum sensing, biofilm formation, metal sensing, motility, survival, and many other functions (Bhagirath et al 2019;Rajput, Kaur, and Kumar 2016) . The antibiotic resistance TCSs help bacteria to survive in the presence of various antibiotics (Tierney and Rather 2019) .…”

“…Further, bacteria also have TCSs in order to survive in other conditions like high pH, metals, anaerobic conditions, nutrient sensing, etc. (Bhagirath et al 2019;Golby et al 1999) . Therefore, the many roles played by TCSs make them a valuable potential target for antimicrobials.…”

The two-component system CopRS maintains femtomolar levels of free copper in the periplasm ofPseudomonas aeruginosausing a phosphatase-based mechanism

“…Cytoplasmic Cu + sensing transcriptional regulators are diverse, as different bacterial species have solved Cu + homeostasis using alternative strategies (1, 5, 20, 21). However, the periplasmic response appears usually regulated by similar t wo- c omponent s ystem (TCS) (22, 23). Although absent in Salmonella (6), many Enterobacteriaceae (e.g., Escherichia coli, Klebsiella pneumoniae, etc. )…”