A comprehensive analysis of the mutational landscape determining polymyxin resistance in Klebsiella pneumoniae

Abstract

Background: Klebsiella pneumoniae poses a critical global health threat due to its increasing resistance to polymyxin, the last-line antibiotic. Outer membrane remodelling, mediated by various two-component systems (TCS), is primarily involved in the development of polymyxin resistance (PolR). This study conducted an in-depth analysis of mutations within TCS-associated genes that contribute to PolR in K. pneumoniae.

Methods: A systematic literature search was conducted in PubMed, Google Scholar, ScienceDirect and Scopus to identify studies reporting TCS-mediated PolR in K. pneumoniae. Data on gene mutations, mutation sites and geographical distribution were extracted. In silico analyses using PROVEAN and DynaMut2 were performed to predict the structural consequences and functional impact of the mutations.

Results: Our study revealed that disruptions in the MgrB protein, primarily through IS elements and amino acid substitutions, are the major drivers of PolR. Additionally, notable mutations were observed in the PhoPQ, PmrAB and CrrAB TCSs among the PolR strains, which may potentially impact the function of these modules. Moreover, several such mutations were found to be located in specific hotspot regions in the protein structure and have a distinct geographical distribution.

Conclusions: This study provides a comprehensive overview of TCS-mediated PolR mechanisms in K. pneumoniae, highlighting the diversity and functional impact of mutations in key regulatory genes. The prevalence of IS elements, particularly in mgrB, and point mutations in mgrB, phoPQ, pmrAB and crrAB underscores the complex evolutionary pathways leading to PolR. Understanding these mechanisms is crucial for developing effective strategies to combat the spread of PolR K. pneumoniae.