Investigating the role of PmrB mutation on Colistin antibiotics drug resistance in Klebsiella Pneumoniae

Abstract

Klebsiella pneumoniae, a member of the Enterobacteriaceae family, naturally resides in the digestive tracts of both healthy animals and humans. Carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a significant health risk for hospitalized patients worldwide, greatly reducing the effectiveness of commonly used antibiotics. This leaves healthcare providers with limited treatment options, often relying on colistin. PmrB is important for the survival of Klebsiella pneumonia and, a mutation in the PmrB protein is accountable for the development of colistin antibiotic resistance in Klebsiella pneumonia. This is especially important because colistin is a fundamental component in the treatment of pneumonia. Three mutated residues—T157P, G207D, and T246A—are responsible for colistin resistance. The structural alterations and underlying mechanisms in the PmrB protein that cause resistance owing to mutation remain unclear. As a result, this study is focused to the exploration of the putative mechanism of resistance resulting from these mutations, as well as the structure modification of normal and mutant PmrB proteins, using molecular docking and molecular dynamics simulations analysis. Our results demonstrated that the interaction paradigm for the mutants has been altered and thus showing a significant effect upon the hydrogen bonding network. Interestingly, the binding of Colistin with the three mutant demonstrate unstable behavior as compared with WT+Colistin. The proposed drug-resistance mechanism will help to guide the development of PmrB drugs. These finding may give a new framework for developing novel drugs against the mutant version of PmrB.