Small regulatory RNAs mediated regulation of virulence and host–pathogen interaction in the Gram-negative ESKAPE pathogens

The emergence and global spread of antimicrobial resistant (AMR) pathogens represent a critical challenge to global public health security. The ESKAPE pathogens refer to a group of highly troublesome multidrug-resistant bacteria responsible for hospital-acquired infections. Of particular concern are Gram-negative ESKAPE pathogens, which pose a significant threat to patient health and healthcare systems worldwide. Systematic investigation into antimicrobial resistance mechanisms and pathogenicity regulation is therefore imperative for developing effective infection control strategies. Emerging evidence highlights small regulatory RNAs (sRNAs) as pivotal post-transcriptional modulators in bacterial physiology, particularly in governing virulence determinant expression and host–pathogen interactions during infection. This review summarizes recent advances in sRNA-mediated regulatory mechanisms in Gram-negative ESKAPE pathogens, with emphasis on Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. We discuss the classification of sRNAs, their regulatory mechanisms, their roles in modulating virulence factors and pathogenicity, as well as the challenges and opportunities in targeting sRNAs for antimicrobial therapy. Evidence accumulated across the studies reviewed indicates that sRNAs exert their function through base pairing with target mRNAs or other sRNA, through interactions with proteins, or as dual-function sRNA. sRNAs have emerged as essential regulators of virulence in the ESKAPE pathogens, influencing capsular polysaccharide production, iron acquisition, biofilm formation, regulation of catabolic pathway genes, cell adhesion and invasion, as well as host immune responses during infection. This review provides a framework for understanding bacterial adaptive evolution through sRNA-mediated regulation and identifies novel intervention targets against multidrug-resistant pathogens.