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

biorxiv. 2020; 
Aditi Deshpande,  Xiaoqian Wu,  Wenwen Huo,  Kelli L. Palmer,  Julian G. Hurdle
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摘要

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 aid genetic studies. We therefore constructed a mismatch repair mutator, in non-toxigenic ATCC 700057, to unbiasedly 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. Allelic deletion of feoB1 in ATCC 700057 reduced intracellular iron content, appearing to sh... More

关键词

Drug resistance evolution, redox stress, iron metabolism