Unexplained Colistin Resistance in Klebsiella pneumoniae: Insights into sRNA-Mediated Post-Transcriptional Regulation.

Abstract

Colistin is a last-resort antibiotic used to treat infections caused by multidrug-resistant Gram-negative pathogens, including Klebsiella pneumoniae. Resistance to colistin can be explained by canonical mechanisms involving chromosomal mutations that activate lipid A modification pathways or by acquisition of plasmid-mediated mcr genes. These mechanisms modify the net charge of the bacterial outer membrane, reducing the binding affinity of colistin. However, an increasing number of genomic surveillance studies report colistin-resistant K. pneumoniae isolates that lack detectable alterations in known resistance mechanisms. This genotype-phenotype discordance suggests that additional regulatory mechanisms may contribute to colistin resistance. This review evaluates the hypothesis that mutation-independent regulatory changes within the PhoP/PhoQ-PmrA/PmrB-CrrA/CrrB signaling network may alter the output of lipid A modification pathways in isolates lacking detectable canonical resistance determinants. This model remains to be experimentally validated. The role of small regulatory RNAs (sRNAs) as potential post-transcriptional modulators of regulatory networks involved in envelope remodeling and antimicrobial susceptibility is explored as a potential explanation for this genotype-phenotype discordance. Finally, experimental approaches including transcriptomics, RNA-RNA interaction mapping, and functional validation are discussed as strategies to study sRNA-mediated regulatory networks. Understanding these regulatory mechanisms may help explain unresolved resistance phenotypes and refine antimicrobial resistance surveillance frameworks.