Open AccessGenome-wide analysis in Escherichia coli unravels a high level of genetic homoplasy associated with cefotaxime resistance
Author(s) -
Jordy P. M. Coolen,
Evert den Drijver,
Jaco J. Verweij,
Jodie A. Schildkraut,
Kornelia Neveling,
Willem J. G. Melchers,
Eva Kolwijck,
Heiman Wertheim,
Jan Kluytmans,
Martijn A. Huynen
Publication year - 2021
Publication title -
microbial genomics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.476
H-Index - 28
ISSN - 2057-5858
DOI - 10.1099/mgen.0.000556
Subject(s) - biology , genetics , escherichia coli , cefoxitin , plasmid , genome , gene , mutation , chromosome , cefotaxime , point mutation , bacteria , staphylococcus aureus
Cefotaxime (CTX) is a third-generation cephalosporin (3GC) commonly used to treat infections caused by Escherichia coli . Two genetic mechanisms have been associated with 3GC resistance in E. coli . The first is the conjugative transfer of a plasmid harbouring antibiotic-resistance genes. The second is the introduction of mutations in the promoter region of the ampC β-lactamase gene that cause chromosome-encoded β-lactamase hyperproduction. A wide variety of promoter mutations related to AmpC hyperproduction have been described. However, their link to CTX resistance has not been reported. We recultured 172 cefoxitin-resistant E. coli isolates with known CTX minimum inhibitory concentrations and performed genome-wide analysis of homoplastic mutations associated with CTX resistance by comparing Illumina whole-genome sequencing data of all isolates to a PacBio sequenced reference chromosome. We mapped the mutations on the reference chromosome and determined their occurrence in the phylogeny, revealing extreme homoplasy at the −42 position of the ampC promoter. The 24 occurrences of a T at the −42 position rather than the wild-type C, resulted from 18 independent C>T mutations in five phylogroups. The −42 C>T mutation was only observed in E. coli lacking a plasmid-encoded ampC gene. The association of the −42 C>T mutation with CTX resistance was confirmed to be significant (false discovery rate T mutation of the ampC promotor as significantly associated with CTX resistance and underlines the role of recurrent mutations in the spread of antibiotic resistance.