Abstract
Colistin (CL) is a last line antibiotic used to treat hospital-associated infections due to multi- and extremely-drug resistant Gram-negative bacterial pathogens, and also in veterinary medicine to treat post-weaning diarrhoea in food animals. Increasing use has led to the emergence of both chromosomal and transferable plasmid-mediated (mcr) colistin resistance in pathogens. While the
chromosomal mechanisms involve mutations in several genes, which also modify the bacterial metabolic pathways, the mcr-mediated mechanism confers low-level colistin resistance, and its role, relevance and fate in mediating colistin resistance in human pathogens remain to be explored. Another phenomenon that remains to be understood is of heteroresistance wherein bacterial subpopulations exhibit different susceptibilities to colistin and can lead to treatment failures during infection. Recent advances in next-generation sequencing have made it possible to study the genome and gene expression at the single cell level. In this project, we intend to study the complexities of resistance and heteroresistance evolution in a population utilizing whole genome sequencing and beyond state of the art NGS techniques of single-cell sequencing and gene expression analysis on pathogenic bacteria, Klebsiella pneumoniae and E. coli, evoluted in vitro under colistin pressure as well as in a mouse model of infection and finally in respiratory samples from patients treated with colistin.
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