Chromosomal Resistance to Metronidazole in Clostridioides difficile can be Mediated by Epistasis Between Iron Homeostasis and Oxidoreductases.

Chromosomal Resistance to Metronidazole in Clostridioides difficile can be Mediated by Epistasis Between Iron Homeostasis and Oxidoreductases. Antimicrob Agents Chemother. 2020 May 26;: Authors: Deshpande A, Wu X, Huo W, Palmer KL, Hurdle JG Abstract Chromosomal resistance to metronidazole has emerged in clinical Clostridioides difficile, but the genetic mechanisms remain unclear. This is further hindered by the inability to generate spontaneous metronidazole-resistant mutants in the lab to interpret genetic variations in clinical isolates. We therefore constructed a mismatch repair mutator, in non-toxigenic ATCC 700057, to survey the mutational landscape for de novo resistance mechanisms. In separate experimental evolutions, the mutator adopted a deterministic path to resistance, with truncation of ferrous iron transporter FeoB1 as a first-step mechanism of low-level resistance. Deletion of feoB1 in ATCC 700057 reduced intracellular iron content, appearing to shift cells toward flavodoxin-mediated oxidoreductase reactions, which are less favorable for metronidazole's cellular action. Higher level resistance evolved from sequential acquisition of mutations to catalytic domains of pyruvate-ferredoxin/flavodoxin oxidoreductase (PFOR encoded by nifJ); a synonymous codon change to putative xdh (xanthine dehydrogenase encoded by CD630_31770), likely affecting mRNA stability; and lastly, frameshift and point mutations that inactivated the ...
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research