Resistance to nonribosomal peptide antibiotics mediated by d-stereospecific peptidases

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Abstract

Nonribosomal peptide antibiotics, including polymyxin, vancomycin, and teixobactin, most of which contain d-amino acids, are highly effective against multidrug-resistant bacteria. However, overusing antibiotics while ignoring the risk of resistance arising has inexorably led to widespread emergence of resistant bacteria. Therefore, elucidation of the emerging mechanisms of resistance to nonribosomal peptide antibiotics is critical to their implementation. Here we describe a networking-associated genome-mining platform for linking biosynthetic building blocks to resistance components associated with biosynthetic gene clusters. By applying this approach to 5,585 complete bacterial genomes spanning the entire domain of bacteria, with subsequent chemical and enzymatic analyses, we demonstrate a mechanism of resistance toward nonribosomal peptide antibiotics that is based on hydrolytic cleavage by d-stereospecific peptidases. Our finding reveals both the widespread distribution and broad-spectrum resistance potential of d-stereospecific peptidases, providing a potential early indicator of antibiotic resistance to nonribosomal peptide antibiotics.

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Fig. 1: Co-occurrence networks reveal the widespread distribution of BGC-associated d-stereospecific peptidases.
Fig. 2: Genetic and metabolic analyses reveal the d-stereospecific hydrolytic activities of DRPs.
Fig. 3: In vitro characterization reveals the d-stereospecific hydrolytic activities of DRPs.
Fig. 4: Biochemical analyses reveal the broad-spectrum resistance of BogQ against peptide antibiotics.

Change history

  • 07 March 2018

    In the version of this article originally published, the links and files for the Supplementary Information, including Supplementary Tables 1–5, Supplementary Figures 1–25, Supplementary Note, Supplementary Datasets 1–4 and the Life Sciences Reporting Summary, were missing in the HTML. The error has been corrected in the HTML version of this article.

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Acknowledgements

This work was generously supported by a grant from the China Ocean Mineral Resources Research and Development Association (COMRRDA17SC01 to P.-Y.Q.). We thank J. Sun and A. Cheung for comments on the manuscript and Y.C. Yan for help with scripts development.

Author information

Y.-X.L., Z.Z., P.H., and W.-P.Z. performed bioinformatics analysis and chemical and biochemical experiments. All authors analyzed and discussed the results. P.-Y. Q. and Y.-X.L. designed the study and prepared the manuscript.

Correspondence to Pei-Yuan Qian.

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Supplementary Text and Figures

Supplementary Tables 1–5, Supplementary Figures 1–25

Life Sciences Reporting Summary

Supplementary Note

Nonribosomal peptide antibiotics resistance mediated by a widespread family of d-stereospecific peptidases

Supplementary Datasets 1–4

Dataset 1 (Bacterial genomes used for biosynthetic analysis) Dataset 2 (Biosynthetic elements and resistance elements) Dataset 3 (Statistical analysis for networking) Dataset 4 (Proteins used for phylogenetic analysis)

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Li, Y., Zhong, Z., Hou, P. et al. Resistance to nonribosomal peptide antibiotics mediated by d-stereospecific peptidases. Nat Chem Biol 14, 381–387 (2018) doi:10.1038/s41589-018-0009-4

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