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

Bacteria sense and respond to environmental stimuli through two-component systems (TCSs), that are composed of histidine kinase sensing and response regulator elements. TCSs are ubiquitous and participate in numerous cellular functions. TCSs across the ESKAPEE pathogens, representing the leading causes of nosocomial infections, were characterized using pangenome analytics, including annotation, mapping, pangenomic status, gene orientation, sequence variation, and structure. Our findings fall into two categories. 1) phylogenetic distribution of TCSs: (i) the number and types of TCSs varies between species of the ESKAPEE pathogens; (ii) TCSs are group-specific, i.e., Gram-positive and Gram-negative, except for KdpDE; (iii) most TCSs are conserved among genomes of an ESKAPEE, except in Pseudomonas aeruginosa . 2) sequence variation: (i) at the operon level, the genomic architecture of a TCS operon stratifies into a few discrete classes; and (ii) at the gene sequence level, histidine kinases, responsible for signal sensing, show sequence and structural variability as compared to response regulators that show a high degree of conservation. Taken together, this first comprehensive pangenomic assessment of TCSs reveals a range of strategies deployed by the ESKAPEE pathogens to manifest pathogenicity and antibiotic resistance. It further suggests that the conserved features of TCSs makes them an attractive group of potential targets with which to address antibiotic resistance. ### Competing Interest Statement The authors have declared no competing interest.