Unstable tandem gene amplification generates heteroresistance (variation in resistance within a population) to colistin in Salmonella enterica.

摘要: Heteroresistance, a phenomenon where subpopulations of bacterial isolate exhibit different susceptibilities to an antibiotic, is growing clinical problem the underlying genetic mechanisms in most cases remain unknown. We isolated colistin resistant mutants Escherichia coli and Salmonella enterica serovar Typhimurium at concentrations colistin. Genetic analysis showed that genetically stable pmrAB point mutations were responsible for resistance during selection high drug both species low E. coli. In contrast, S. selected concentrations, amplification large chromosomal regions conferred heteroresistant phenotype. All amplifications included pmrD gene, which encodes positive regulator up-regulates proteins modify lipid A, as result increase resistance. Inactivation over-expression gene prevented resistance, respectively, demonstrating PmrD protein required sufficient confer The heteroresistance phenotype explained by variable dosage population, sub-populations with copy number show levels propose variability genes can explain observed clinically pathogenic bacteria.