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

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

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.

Highlights

The Escherichia coli microcin C (McC) and related compounds are potent Trojan horse peptide-nucleotide antibiotics
We show that bacterial MccH, a product of a gene in an mcc-like cluster from Hyalangium minutum, as well as its homologs from Salmonella enterica, Nocardiopsis kunsanensis, and Pseudomonas fluorescens, are phosphoramidases that confer resistance to McC-like compounds by hydrolyzing the toxic aspartamideadenylate that is produced after intracellular processing of peptidyl-nucleotides
In this work, we uncover a novel mechanism of immunity to microcin C-like compounds by MccHHmi, a HIT-like phosphoramidase encoded in the mcc cluster of H. minutum

Summary

Introduction

The Escherichia coli microcin C (McC) and related compounds are potent Trojan horse peptide-nucleotide antibiotics. The peptide part is degraded by nonspecific peptidases releasing an aspartamide-adenylate containing a phosphoramide bond. McC1120 is further modified by MccD and the N-terminal domain of MccE protein, whose joint action results in a fully matured microcin C, McC1177, harboring an aminopropyl decoration on the phosphate moiety (Fig. 1) [4]. Both forms of McC are exported from the producing cell by a specialized transporter encoded by the mccC gene [5]. Processed McC competitively inhibits AspRS, bringing protein biosynthesis to a halt [5]

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Conclusion