Genetic Diversity of Polymyxin Resistance Genes in Klebsiella pneumoniae Clinical Isolates

This study investigates the genetic diversity and evolutionary mechanisms driving polymyxin resistance in Klebsiella pneumoniae , a critical priority pathogen. By analysing mgrB , phoPQ and pmrAB genes in susceptible (PM‐S) and resistant (PM‐R) populations through neutrality tests (Tajima D , Fu & Li's D ) we uncovered polygenic adaptation and positive selection as a key driver of resistance. High genetic diversity was observed across all loci , with mgrB insertions dominating PM‐R populations. Negative Tajima and Fu & Li's D values and excess rare alleles revealed recent population expansions linked to the reintroduction of polymyxins in the 2010s. Positive selection via selective sweeps was detected in PM‐R isolates, exemplified by the rapid spread of haplotype 27, which presents mgrB insertions, the major determinant of LPS modification pathway hyperactivation. The expansion of this haplotype suggests that horizontal gene transfer accelerates resistance dissemination. The elevated genetic diversity observed in the phoPQ and pmrAB systems among isolates harbouring mgrB alterations may reflect reduced adaptive fitness costs, enabling the preservation of genomic variability despite sustained selective pressures. Our results demonstrate that polymyxin resistance arises through polygenic adaptation and positive selection, combining de novo mutations, recombination and selection‐driven sweeps. These dynamics threaten to exacerbate resistance in hospital environments, emphasising the need for genomic surveillance and alternative therapies. This study bridges molecular evolution and clinical epidemiology, offering insights into the resilience of K. pneumoniae and the ecological drivers of antimicrobial resistance.