Daptomycin-Mediated Reorganization of Membrane Architecture Causes Mislocalization of Essential Cell Division Proteins
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Daptomycin is a lipopeptide antibiotic used clinically for the treatment of certain types of Gram-positive infections, including those caused by methicillin-resistant Staphylococcus aureus (MRSA). Details of the mechanism of action of daptomycin continue to be elucidated, particularly the question of whether daptomycin acts on the cell membrane, the cell wall, or both. Here, we use fluorescence microscopy to directly visualize the interaction of daptomycin with the model Gram-positive bacterium Bacillus subtilis. We show that the first observable cellular effects are the formation of membrane distortions (patches of membrane) that precede cell death by more than 30 min. Membrane patches are able to recruit the essential cell division protein DivIVA. Recruitment of DivIVA correlates with membrane defects and changes in cell morphology, suggesting a localized alteration in the activity of enzymes involved in cell wall synthesis that could account for previously described effects of daptomycin on cell wall morphology and septation. Membrane defects colocalize with fluorescently labeled daptomycin, DivIVA, and fluorescent reporters of peptidoglycan biogenesis (Bocillin FL and BODIPY FL-vancomycin), suggesting that daptomycin plays a direct role in these events. Our results support a mechanism for daptomycin with a primary effect on cell membranes that in turn redirects the localization of proteins involved in cell division and cell wall synthesis, causing dramatic cell wall and membrane defects, which may ultimately lead to a breach in the cell membrane and cell death. These results help resolve the longstanding questions regarding the mechanism of action of this important class of antibiotics.
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Stationary growth-phase conditions make it less likely that bacterial cell wall-active antibiotics (β-lactams and glycopeptides) are optimally effective.
“In addition, the stationary growth-phase conditions make it less likely that bacterial cell wall-active antibiotics (β-lactams and glycopeptides) are optimally effective.[77][78][79]”
From Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association (2015) · cites this paper as [78]
The Introduction identifies vancomycin and oxacillin as cell wall-active antibiotics, but does not discuss their effectiveness during stationary-phase growth. A References entry mentions stationary-phase cells only in the title of a study about daptomycin. Searches for stationary-phase efficacy of β-lactams and glycopeptides found no passage addressing the claim. (LLM, conf=0.75)
Experimental — accuracy not yet measuredRecent evidence suggests that DAP mainly targets the CM at the level of the division septum.
“Of note, recent evidence suggests that DAP mainly targets the CM at the level of the division septum (86).”
From Mechanisms of Antibiotic Resistance (2016) · cites this paper as [86]
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Self-citation
- Authors
- Pogliano, J., Pogliano, N., & Silverman, J. A.
- Affiliations
- University of California San Diego (US)
- Cubist Pharmaceuticals (United States) (US)
- ORCID
- Pogliano, J.
- Venue
- Journal of Bacteriology
- Publisher
- American Society for Microbiology
- Published
- 2012-06-01
- Volume
- 194
- Issue
- 17
- Pages
- 4494-4504
- ISSN
- 0021-9193 (ISSN-L)
- PMC
- PMC3415520
- OpenAlex
- W2113063737
- Cited by
- 319
- References
- 59
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 23 · 2023: 19 · 2022: 23 · 2021: 22 · 2020: 27 · 2019: 27 · 2018: 23 · 2017: 30 · 2016: 30 · 2015: 29 · 2014: 25 · 2013: 18 · 2012: 5
- FWCI
- 14.84
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Journal of Bacteriology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM073898, GM073898)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Health Sciences › Medicine › Infectious Diseases › Antimicrobial Resistance in Staphylococcus
- Life Sciences › Immunology and Microbiology › Microbiology › Antimicrobial Peptides and Activities
- Keywords
- daptomycin, antibiotic mechanism of action, membrane deformation, DivIVA, cell division proteins, cell wall biosynthesis, Bacillus subtilis, methicillin-resistant Staphylococcus aureus, cell morphology, septation
- MeSH terms
- Anti-Bacterial Agents, Bacillus subtilis, Bacterial Proteins, Cell Division, Cell Membrane, Cell Wall, Microbial Sensitivity Tests, Microscopy, Fluorescence, Peptidoglycan, Daptomycin, Cell Cycle Proteins
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