Rule-based omics mining reveals antimicrobial macrocyclic peptides against drug-resistant clinical isolates

Zhuo Cheng, Bei-Bei He, Kangfan Lei, Ying Gao, Yuqi Shi, Zheng Zhong, Hongyan Liu, Runze Liu, Haili Zhang, Song Wu, Wenxuan Zhang (), Xiaoyu Tang () and Yong-Xin Li ()
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Zhuo Cheng: The University of Hong Kong
Bei-Bei He: The University of Hong Kong
Kangfan Lei: Chinese Academy of Medical Sciences and Peking Union Medical College
Ying Gao: The University of Hong Kong
Yuqi Shi: The University of Hong Kong
Zheng Zhong: The University of Hong Kong
Hongyan Liu: The University of Hong Kong
Runze Liu: The University of Hong Kong
Haili Zhang: Shenzhen Bay Laboratory
Song Wu: Chinese Academy of Medical Sciences and Peking Union Medical College
Wenxuan Zhang: Chinese Academy of Medical Sciences and Peking Union Medical College
Xiaoyu Tang: Shenzhen Bay Laboratory
Yong-Xin Li: The University of Hong Kong

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Antimicrobial resistance remains a significant global threat, driving up mortality rates worldwide. Ribosomally synthesized and post-translationally modified peptides have emerged as a promising source of novel peptide antibiotics due to their diverse chemical structures. Here, we report the discovery of new aminovinyl-(methyl)cysteine (Avi(Me)Cys)-containing peptide antibiotics through a synergistic approach combining biosynthetic rule-based omics mining and heterologous expression. We first bioinformatically identify 1172 RiPP biosynthetic gene clusters (BGCs) responsible for Avi(Me)Cys-containing peptides formation from a vast pool of over 50,000 bacterial genomes. Subsequently, we successfully establish the connection between three identified BGCs and the biosynthesis of five peptide antibiotics via biosynthetic rule-guided metabolic analysis. Notably, we discover a class V lanthipeptide, massatide A, which displays excellent activity against gram-positive pathogens, including drug-resistant clinical isolates like linezolid-resistant S. aureus and methicillin-resistant S. aureus, with a minimum inhibitory concentration of 0.25 μg/mL. The remarkable performance of massatide A in an animal infection model, coupled with a relatively low risk of resistance and favorable safety profile, positions it as a promising candidate for antibiotic development. Our study highlights the potential of Avi(Me)Cys-containing peptides in expanding the arsenal of antibiotics against multi-drug-resistant bacteria, offering promising drug leads in the ongoing battle against infectious diseases.

Date: 2024
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DOI: 10.1038/s41467-024-49215-y

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