Histidine-triad hydrolases provide resistance to peptide- nucleotide antibiotics

Eldar Yagmurov, Darya Tsibulskaya, Alexey Livenskyi, Marina Serebryakova, Yury I. Wolf, Sergei Borukhov, Konstantin Severinov, Svetlana Dubiley

    Research output: Contribution to journalArticlepeer-review

    4 Citations (Scopus)


    The Escherichia coli microcin C (McC) and related compounds are potent Trojan horse peptide-nucleotide antibiotics. The peptide part facilitates transport into sensitive cells. Inside the cell, the peptide part is degraded by nonspecific peptidases releasing an aspartamide-adenylate containing a phosphoramide bond. This nonhydrolyzable compound inhibits aspartyl-tRNA synthetase. In addition to the efficient export of McC outside the producing cells, special mechanisms have evolved to avoid self-toxicity caused by the degradation of the peptide part inside the producers. Here, we report that histidine-triad (HIT) hydrolases encoded in biosynthetic clusters of some McC homologs or by standalone genes confer resistance to McC-like compounds by hydrolyzing the phosphoramide bond in toxic aspartamide-adenosine, rendering them inactive. IMPORTANCE Uncovering the mechanisms of resistance is a required step for countering the looming antibiotic resistance crisis. In this communication, we show how universally conserved histidine-triad hydrolases provide resistance to microcin C, a potent inhibitor of bacterial protein synthesis.

    Original languageEnglish
    Article numbere00497-20
    Issue number2
    Publication statusPublished - 1 Mar 2020


    • Antibiotics
    • HinT
    • Histidine-triad proteins
    • Microcin C
    • Peptidenucleotides
    • RiPPs


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