Histidine-Triad Hydrolases Provide Resistance to Peptide-Nucleotide Antibiotics

mBio

Eldar Yagmurov¹  Konstantin Severinov¹  Darya Tsibulskaya¹  Svetlana Dubiley¹  Sergei Borukhov²  Alexey Livenskyi³  Marina Serebryakova³  Yury I. Wolf⁴ 

[1] Center for Life Sciences, Skolkovo Institute of Science and Technology, Skolkovo, Russia;Department of Cell Biology and Neuroscience, Rowan University School of Osteopathic Medicine, Stratford, New Jersey, USA;Institute of Gene Biology, Russian Academy of Science, Moscow, Russia;National Center for Biotechnology Information, National Library of Medicine, Bethesda, Maryland, USA;

关键词: HinT;    RiPPs;    antibiotics;    histidine-triad proteins;    microcin C;    peptide-nucleotides;   

DOI  :  10.1128/mBio.00497-20

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown