ArticleNature microbiology2022
ClpP inhibitors are produced by a widespread family of bacterial gene clusters.
Article in Nature microbiology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 49 citations in OpenAlex.
- Self-resistance as a guide to discovering bioactive natural products.Current opinion in chemical biology · 2026Review
- Resistance-CONKAT-seq Guided Discovery of a ClpP Active Natural Product from a Soil Metagenome.ACS chemical biology · 2026Article
- Article
- Fred Goldberg machines in the pathogenesis of Mycobacterium tuberculosis.The Journal of biological chemistry · 2026Review
- ClpP2 modulates ClpXP assembly to promote multiple pathogenic phenotypes inProceedings of the National Academy of Sciences of the United States of America · 2026Article
- Proteostasis-targeted antibacterial strategies.Journal of microbiology (Seoul, Korea) · 2026Review
- An integrated complete-genome sequencing and systems biology approach to predict antimicrobial resistance genes in the virulent bacterial strains of Moraxella catarrhalis.Briefings in functional genomics · 2026Article
- Polydatin as a natural ClpP modulator for combating methicillin-resistantFrontiers in cellular and infection microbiology · 2026Article
- Inhibitory Effect of Amentoflavone on the Virulence of MRSA by Targeting ClpP.Journal of cellular and molecular medicine · 2025Article
- Chemotype- and Target-Driven Genome Mining for a New Natural Product Inhibitor of Bacterial Peptide Deformylase.Journal of the American Chemical Society · 2025Article
- Genomic Repertoire of Twenty-Two Novel Vibrionaceae Species Isolated from Marine Sediments.Microbial ecology · 2025Article
- Synthetic Biology in Natural Product Biosynthesis.Chemical reviews · 2025Review
- Article
- Self-resistance-gene-guided, high-throughput automated genome mining of bioactive natural products from Streptomyces.Cell systems · 2025Article
- Molecular basis for azetidine-2-carboxylic acid biosynthesis.Nature communications · 2025Article
- Metagenomic study of lake microbial mats reveals protease-inhibiting antiviral peptides from a core microbiome member.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Review
- Article
- Identification and application of a strong bidirectionalEngineering microbiology · 2024Article
- Interplay of emerging and established technologies drives innovation in natural product antibiotic discovery.Current opinion in microbiology · 2023Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
The caseinolytic protease (ClpP) is part of a highly conserved proteolytic complex whose disruption can lead to antibacterial activity but for which few specific inhibitors have been discovered. Specialized metabolites produced by bacteria have been shaped by evolution for specific functions, making them a potential source of selective ClpP inhibitors. Here, we describe a target-directed genome mining strategy for discovering ClpP-interacting compounds by searching for biosynthetic gene clusters that contain duplicated copies of ClpP as putative antibiotic resistance genes. We identify a widespread family of ClpP-associated clusters that are known to produce pyrrolizidine alkaloids but whose connection to ClpP has never been made. We show that previously characterized molecules do not affect ClpP function but are shunt metabolites derived from the genuine product of these gene clusters, a reactive covalent ClpP inhibitor. Focusing on one such cryptic gene cluster from Streptomyces cattleya, we identify the relevant inhibitor, which we name clipibicyclene, and show that it potently and selectively inactivates ClpP. Finally, we solve the crystal structure of clipibicyclene-modified Escherichia coli ClpP. Clipibicyclene's discovery reveals the authentic function of a family of natural products whose specificity for ClpP and abundance in nature illuminate the role of eco-evolutionary forces during bacterial competition.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.