Histidine-Triad Hydrolases Provide Resistance to Peptide-Nucleotide Antibiotics.

Authors

Eldar Yagmurov, Skolkovo Institute of Science and Technology
Darya Tsibulskaya, Skolkovo Institute of Science and Technology
Alexey Livenskyi, Russian Academy of Sciences
Marina Serebryakova, Russian Academy of Sciences
Yury I Wolf, NCBI, National Library of Medicine
Sergei Borukhov, Rowan University School of Osteopathic Medicine
Konstantin Severinov, Skolkovo Institute of Science and Technology
Svetlana Dubiley, Skolkovo Institute of Science and Technology

Document Type

Article

Version Deposited

Published Version

Publication Date

4-7-2020

Publication Title

mBio

DOI

10.1128/mBio.00497-20

Abstract

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.

Recommended Citation

Yagmurov E, Tsibulskaya D, Livenskyi A, Serebryakova M, Wolf YI, Borukhov S, Severinov K, Dubiley S. Histidine-triad hydrolases provide resistance to peptide-nucleotide antibiotics. mBio. 2020 Apr 7;11(2). pii: e00497-20. doi: 10.1128/mBio.00497-20. PMID: 32265328. PMCID: PMC7157772.

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This work is licensed under a Creative Commons Attribution 4.0 International License.