ArticleNature2013
Activated ClpP kills persisters and eradicates a chronic biofilm infection.
Article in Nature, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 350 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
350 citing papers in PubMed, 666 citations in OpenAlex.
- A multicenter randomized placebo controlled trial of rifampin to reduce pedal amputations for osteomyelitis in veterans with diabetes (VA INTREPID).BMC infectious diseases · 2020Trial
- Global proteolysis during starvation governs proteome remodeling and a survival-regrowth trade-off in bacteria.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Small-molecule activators of theiScience · 2026Article
- Heteroresistance tolerance and persistence in antibiotic treatment failure.Folia microbiologica · 2026Review
- From Planktonic to Sedentary Lifestyle: Molecular Dissection of the Establishment and Maintenance of Mycobacterial Biofilm.ACS omega · 2026Article
- Targeting ClpP Protease: Emerging Therapeutic Strategies and Small-Molecule Modulators in Drug Discovery.Medicinal research reviews · 2026Review
- Characterization of Antibiotic-Tolerant Persister Cells inAnimals : an open access journal from MDPI · 2026Article
- The Pharmacology of Bacterial Persistence: From Antibiotic Tolerance to Antimicrobial Resistance.Antibiotics (Basel, Switzerland) · 2026Review
- Unveiling the antibacterial activity and mechanisms of BMS-303141 against Staphylococcus aureus.BMC microbiology · 2026Article
- Repurposing Birabresib to target Gram‑positive bacteria.npj antimicrobials and resistance · 2026Article
- Drug repurposing: antimicrobial and antibiofilm effects of MLS0315771 against Gram-positive bacteria.BMC microbiology · 2026Article
- Differential contributions of ClpX and ClpP to pulmonary virulence in classical and hypervirulentInfection and immunity · 2026Article
- CAMPER: mechanistic artificial intelligence for designing peptides that target MRSA persisters.Nature communications · 2026Article
- Expression patterns of core metabolic genes and elevated intracellular ROS confer drug tolerance inMicrobiology spectrum · 2026Article
- Proteostasis-targeted antibacterial strategies.Journal of microbiology (Seoul, Korea) · 2026Review
- A small molecule allosterically activates SecA dependent secretion.Communications biology · 2026Article
- Methicillin-resistant and susceptible Staphylococcus aureus: tolerance, immune evasion and treatment.Nature reviews. Microbiology · 2026Review
- Structural and mechanistic insights into caseinolytic protease inhibition for antimicrobial development against Pseudomonas plecoglossicida.PLoS pathogens · 2026Article
- Enzymes-enhanced antibiotic therapy reduces biofilms to undetectable levels in an implant-associated infection model.NPJ biofilms and microbiomes · 2026Article
- Strategies for biofilm inhibition: the role of synthetic drug- and nanotechnology-based agents.Archives of microbiology · 2025Review
290 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
Chronic infections are difficult to treat with antibiotics but are caused primarily by drug-sensitive pathogens. Dormant persister cells that are tolerant to killing by antibiotics are responsible for this apparent paradox. Persisters are phenotypic variants of normal cells and pathways leading to dormancy are redundant, making it challenging to develop anti-persister compounds. Biofilms shield persisters from the immune system, suggesting that an antibiotic for treating a chronic infection should be able to eradicate the infection on its own. We reasoned that a compound capable of corrupting a target in dormant cells will kill persisters. The acyldepsipeptide antibiotic (ADEP4) has been shown to activate the ClpP protease, resulting in death of growing cells. Here we show that ADEP4-activated ClpP becomes a fairly nonspecific protease and kills persisters by degrading over 400 proteins, forcing cells to self-digest. Null mutants of clpP arise with high probability, but combining ADEP4 with rifampicin produced complete eradication of Staphylococcus aureus biofilms in vitro and in a mouse model of a chronic infection. Our findings indicate a general principle for killing dormant cells-activation and corruption of a target, rather than conventional inhibition. Eradication of a biofilm in an animal model by activating a protease suggests a realistic path towards developing therapies to treat chronic infections.
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What OpenQuestion holds
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.