Resistance to nonribosomal peptide antibiotics mediated by D-stereospecific peptidases

Nature Chemical Biology
Yong-Xin LiPei-Yuan Qian

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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Citations

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Datasets Mentioned

BETA
KY810814

Methods Mentioned

BETA
NMR
Protein Assay
PCR
cleavage assay

Software Mentioned

PDB2PQR
ape
Chimera
OriginPro
sgRNA Designer
GenScript
HyStar chromatography Compass DataAnalysis
BLASTP
MODEL
Mega7

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