Cardiolipin Prevents Membrane Translocation and Permeabilization by Daptomycin
Open accessAbstract
Daptomycin is an acidic lipopeptide antibiotic that, in the presence of calcium, forms oligomeric pores on membranes containing phosphatidylglycerol. It is clinically used against various Gram-positive bacteria such as Staphylococcus aureus and Enterococcus species. Genetic studies have indicated that an increased content of cardiolipin in the bacterial membrane may contribute to bacterial resistance against the drug. Here, we used a liposome model to demonstrate that cardiolipin directly inhibits membrane permeabilization by daptomycin. When cardiolipin is added at molar fractions of 10 or 20% to membranes containing phosphatidylglycerol, daptomycin no longer forms pores or translocates to the inner membrane leaflet. Under the same conditions, daptomycin continues to form oligomers; however, these oligomers contain only close to four subunits, which is approximately half as many as observed on membranes without cardiolipin. The collective findings lead us to propose that a daptomycin pore consists of two aligned tetramers in opposite leaflets and that cardiolipin prevents the translocation of tetramers to the inner leaflet, thereby forestalling the formation of complete, octameric pores. Our findings suggest a possible mechanism by which cardiolipin may mediate resistance to daptomycin, and they provide new insights into the action mode of this important antibiotic.
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Cardiolipin (CL) seems to play an important role in the translocation of DAP oligomers from the outer to the inner leaflet, but its contribution is not completely understood.
“Additionally, another phospholipid (cardiolipin, CL), seems to play an important role in the translocation of DAP oligomers from the outer of the inner leaflet, but its contribution is not completely understood.”
From Mechanisms of Antibiotic Resistance (2016) · cites this paper as [87]
There is evidence to suggest that the presence of CL in high concentrations may prevent translocation of DAP oligomers into the inner leaflet of the phospholipid bilayer.
“In fact, there is evidence to suggest that the presence of CL in high concentrations may prevent translocation of DAP oligomers into the inner leaflet of the phospholipid bilayer (87).”
From Mechanisms of Antibiotic Resistance (2016) · cites this paper as [87]
DAP's oligomerization at the outer leaflet of the CM appears to be dependent on the presence of the phospholipid phosphatidylglycerol (PG).
“DAP’s oligomerization at the outer leaflet of the CM appears to be dependent on the presence of the phospholipid phosphatidylglycerol (PG) (87).”
From Mechanisms of Antibiotic Resistance (2016) · cites this paper as [87]
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- Authors
- Zhang, T., Muraih, J. K., Tishbi, N., Herskowitz, J., Victor, R. L., Silverman, J., Uwumarenogie, S., Taylor, S. D., Palmer, M., & Mintzer, E.
- Affiliations
- University of Waterloo (CA)
- Al-Muthanna University (IQ)
- Yeshiva University (US)
- Cubist Pharmaceuticals (United States) (US)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 289
- Issue
- 17
- Pages
- 11584-11591
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4002069
- OpenAlex
- W2019723157
- Cited by
- 162
- References
- 27
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 14 · 2023: 10 · 2022: 17 · 2021: 8 · 2020: 21 · 2019: 12 · 2018: 15 · 2017: 9 · 2016: 22 · 2015: 13 · 2014: 7
- FWCI
- 13.84
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Touro Scholar (Touro College) (submittedVersion)
- UWSpace (University of Waterloo) (submittedVersion)
- Funders
- California HIV/AIDS Research Program
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada
- Topics
- Life Sciences › Immunology and Microbiology › Microbiology › Antimicrobial Peptides and Activities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- daptomycin, cardiolipin, membrane permeabilization, antibiotic resistance, lipopeptide antibiotics, phosphatidylglycerol, pore formation, bacterial membranes, liposome model, Staphylococcus aureus, Enterococcus
- MeSH terms
- Anti-Bacterial Agents, Biological Transport, Calorimetry, Cardiolipins, Cell Membrane Permeability, Gram-Positive Bacteria, Daptomycin
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