In-silico Analysis of a Novel MCR-1.1 Variant on an IncX4 Plasmid Attenuating Colistin Resistance in Multidrug-Resistant ST131.

INTRODUCTION

The emergence of mcr-1.1-mediated colistin resistance in poses a significant threat to last-resort antibiotic therapy. This study investigates a novel variant of mcr-1.1 found in a highly virulent E. coli ST131 strain isolated from a pediatric patient with severe aplastic anemia and recurrent infections.

METHODS

Blood samples were collected from a 4-year-old patient, and the isolate underwent antimicrobial susceptibility testing, multi-locus sequence typing, serotyping, and whole-genome sequencing. In-silico analyses included molecular docking and molecular dynamics simulations to assess the structural and functional impact of the mcr-1.1 variant. Horizontal gene transfer experiments evaluated plasmid mobility.

RESULTS

The ST131 isolate harboured a mcr-1.1 gene located on a stable IncX4 plasmid and exhibited a multidrug-resistant phenotype. A missense mutation (T797C) led to an F265L substitution in the MCR-1.1 enzyme, reducing its phosphoethanolamine transferase activity. This mutation likely impairs lipid A modification, decreasing colistin resistance. Molecular modeling supported the reduced binding affinity of the mutated MCR-1.1 for lipid A. The plasmid demonstrated a horizontal transfer frequency of 1.3 × 10². Phylogenetic analysis showed close relatedness to global ST131 clones.

CONCLUSION

This novel mcr-1.1 variant potentially restores colistin susceptibility in a globally prevalent lineage. The findings highlight a unique resistance attenuation mechanism and offer a promising avenue for restoring colistin efficacy. Further validation is warranted to explore therapeutic strategies exploiting such mutations.