ArticleACS chemical biology2013
Antibacterial activity of and resistance to small molecule inhibitors of the ClpP peptidase.
Article in ACS chemical biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 72 citations in OpenAlex.
- Phosphoarginine modulates oligomerization and repressor activity of mycobacterial ClpC2.bioRxiv : the preprint server for biology · 2026Article
- 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
- Discovery of coniferaldehyde as an inhibitor of caseinolytic protease to combat Staphylococcus aureus infections.Molecular medicine (Cambridge, Mass.) · 2025Article
- Decoding the Penicillin-Binding Proteins with Activity-Based Probes.Accounts of chemical research · 2025Review
- Antimicrobial Activity of a Synthetic Brevibacillin Analog Against Multidrug-ResistantInternational journal of molecular sciences · 2025Article
- ClpS Directs Degradation of N-Degron Substrates With Primary Destabilizing Residues in Mycolicibacterium smegmatis.Molecular microbiology · 2025Article
- Interactome Analysis Identifies MSMEI_3879 as a Substrate of Mycolicibacterium smegmatis ClpC1.Microbiology spectrum · 2023Article
- Acyldepsipeptide Antibiotics and a Bioactive Fragment Thereof Differentially PerturbACS chemical biology · 2023Article
- Chemoproteomic Approaches for Unraveling Prokaryotic Biology.Israel journal of chemistry · 2023Article
- Degradation Mechanism of AAA+ Proteases and Regulation ofBiomolecules · 2022Review
- Identification of Arginine Phosphorylation in Mycolicibacterium smegmatis.Microbiology spectrum · 2022Article
- The Development of the Bengamides as New Antibiotics against Drug-Resistant Bacteria.Marine drugs · 2022Review
- ClpP inhibitors are produced by a widespread family of bacterial gene clusters.Nature microbiology · 2022Article
- Nonredundant functions of Mycobacterium tuberculosis chaperones promote survival under stress.Molecular microbiology · 2021Article
- Comparison of Bioorthogonal β-Lactone Activity-Based Probes for Selective Labeling of Penicillin-Binding Proteins.Chembiochem : a European journal of chemical biology · 2021Article
- Identifying the essential genes of Mycobacterium avium subsp. hominissuis with Tn-Seq using a rank-based filter procedure.Scientific reports · 2020Article
- Chemical tools for selective activity profiling of bacterial penicillin-binding proteins.Methods in enzymology · 2020Article
- ClpP Protease, a Promising Antimicrobial Target.International journal of molecular sciences · 2019Review
- ClpP protease activation results from the reorganization of the electrostatic interaction networks at the entrance pores.Communications biology · 2019Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
There is rapidly mounting evidence that intracellular proteases in bacteria are compelling targets for antibacterial drugs. Multiple reports suggest that the human pathogen Mycobacterium tuberculosis and other actinobacteria may be particularly sensitive to small molecules that perturb the activities of self-compartmentalized peptidases, which catalyze intracellular protein turnover as components of ATP-dependent proteolytic machines. Here, we report chemical syntheses and evaluations of structurally diverse β-lactones, which have a privileged structure for selective, suicide inhibition of the self-compartmentalized ClpP peptidase. β-Lactones with certain substituents on the α- and β-carbons were found to be toxic to M. tuberculosis. Using an affinity-labeled analogue of a bioactive β-lactone in a series of chemical proteomic experiments, we selectively captured the ClpP1P2 peptidase from live cultures of two different actinobacteria that are related to M. tuberculosis. Importantly, we found that the growth inhibitory β-lactones also inactivate the M. tuberculosis ClpP1P2 peptidase in vitro via formation of a covalent adduct at the ClpP2 catalytic serine. Given the potent antibacterial activity of these compounds and their medicinal potential, we sought to identify innate mechanisms of resistance. Using a genome mining strategy, we identified a genetic determinant of β-lactone resistance in Streptomyces coelicolor, a non-pathogenic relative of M. tuberculosis. Collectively, these findings validate the potential of ClpP inhibition as a strategy in antibacterial drug development and define a mechanism by which bacteria could resist the toxic effects of ClpP inhibitors.
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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.