Modifications in the pmrB gene are the primary mechanism for the development of chromosomally encoded resistance to polymyxins in uropathogenic Escherichia coli

The Journal of Antimicrobial Chemotherapy
Minh-Duy PhanMark A Schembri

Abstract

Polymyxins remain one of the last-resort drugs to treat infections caused by MDR Gram-negative pathogens. Here, we determined the mechanisms by which chromosomally encoded resistance to colistin and polymyxin B can arise in the MDR uropathogenic Escherichia coli ST131 reference strain EC958. Two complementary approaches, saturated transposon mutagenesis and spontaneous mutation induction with high concentrations of colistin and polymyxin B, were employed to select for mutations associated with resistance to polymyxins. Mutants were identified using transposon-directed insertion-site sequencing or Illumina WGS. A resistance phenotype was confirmed by MIC and further investigated using RT-PCR. Competitive growth assays were used to measure fitness cost. A transposon insertion at nucleotide 41 of the pmrB gene (EC958pmrB41-Tn5) enhanced its transcript level, resulting in a 64- and 32-fold increased MIC of colistin and polymyxin B, respectively. Three spontaneous mutations, also located within the pmrB gene, conferred resistance to both colistin and polymyxin B with a corresponding increase in transcription of the pmrCAB genes. All three mutations incurred a fitness cost in the absence of colistin and polymyxin B. This study identi...Continue Reading

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Citations

Mar 9, 2018·Journal of Clinical Microbiology·Konrad GwozdzinskiTrinad Chakraborty
Mar 14, 2019·The Journal of Antimicrobial Chemotherapy·Anne Sophie BourrelUNKNOWN IAME Resistance Group
Aug 20, 2019·Open Forum Infectious Diseases·Zekun LiQiwen Yang
Nov 27, 2019·Microbial Drug Resistance : MDR : Mechanisms, Epidemiology, and Disease·Jinhu HuangLiping Wang
Nov 20, 2020·Science Translational Medicine·David M P De OliveiraMark J Walker
Oct 30, 2020·Infection and Drug Resistance·Wenli LiaoTieli Zhou

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