Dysregulation of bacterial proteolytic machinery by a new class of antibiotics
Abstract
Here we show that a new class of antibiotics-acyldepsipeptides-has antibacterial activity against Gram-positive bacteria in vitro and in several rodent models of bacterial infection. The acyldepsipeptides are active against isolates that are resistant to antibiotics in clinical application, implying a new target, which we identify as ClpP, the core unit of a major bacterial protease complex. ClpP is usually tightly regulated and strictly requires a member of the family of Clp-ATPases and often further accessory proteins for proteolytic activation. Binding of acyldepsipeptides to ClpP eliminates these safeguards. The acyldepsipeptide-activated ClpP core is capable of proteolytic degradation in the absence of the regulatory Clp-ATPases. Such uncontrolled proteolysis leads to inhibition of bacterial cell division and eventually cell death.
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Acyldepsipeptides have antimicrobial activity by making cytoplasmic proteases constitutively active.
“This fact is underscored by the antimicrobial activity of acyldepsipeptides which render cytoplasmic proteases constitutively active [52].”
From A battle for iron: host sequestration and Staphylococcus aureus acquisition (2012) · cites this paper as [52]
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“This fact is underscored by the antimicrobial activity of acyldepsipeptides which render cytoplasmic proteases constitutively active [52].”
BackgroundBacterial Proteases and Virulence
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- Authors
- Brötz-Oesterhelt, H., Beyer, D., Kroll, H.-P., Endermann, R., Ladel, C., Schroeder, W., Hinzen, B., Raddatz, S., Paulsen, H., Henninger, K., Bandow, J. E., Sahl, H.-G., & Labischinski, H.
- Affiliations
- Bayer (Germany) (DE)
- Universität Greifswald (DE)
- University of Bonn (DE)
- Venue
- Nature Medicine
- Published
- 2005-10-01
- Volume
- 11
- Issue
- 10
- Pages
- 1082-1087
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2163562422
- Cited by
- 505
- References
- 23
- Citations by year
- 2026: 21 · 2025: 23 · 2024: 23 · 2023: 24 · 2022: 31 · 2021: 26 · 2020: 36 · 2019: 31 · 2018: 25 · 2017: 25 · 2016: 27 · 2015: 26 · 2014: 33 · 2013: 39 · 2012: 15
- FWCI
- 5.02
- Type
- journal article
- Language
- en
- Update notices
- erratum (2005-12-01)
- Open access
- closed
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Bayer HealthCare
- Deutsche Forschungsgemeinschaft
- Universiteit van Amsterdam
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Immunology and Microbiology › Microbiology › Antimicrobial Peptides and Activities
- Keywords
- ClpP, bacterial proteolysis, Gram-positive bacteria, antibiotic resistance, antibacterial activity, bacterial cell division inhibition, bacterial cell death, novel antibiotic targets
- MeSH terms
- Animals, Anti-Bacterial Agents, Bacillus subtilis, Bacteria, Escherichia coli, Female, Mutation, Pneumococcal Infections, Protein Binding, Protein Processing, Post-Translational, Molecular Structure, Rats, Wistar, Sepsis, Drug Resistance, Multiple, Bacterial, Escherichia coli Proteins, Depsipeptides, Endopeptidase Clp, Mice, Rats
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