Daptomycin is a last-resort antibiotic that is used against resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA). Although it is a membrane-targeting antibiotic, its exact mechanism of action was unknown. Müller et al. used Bacillus subtilis to determine the effects of daptomycin. They observed that fluorescently labelled daptomycin colocalized with a lipid-mimicking dye that specifically stains membrane regions that contain many fluid lipids. This interaction decreased membrane fluidity, which led to the detachment of enzymes that are responsible for cell wall and lipid synthesis. In contrast to the role of lipid binding in the activity of daptomycin, Pader et al. showed that bacteria can also take advantage of this mechanism for resistance. The authors found that S. aureus sheds phospholipids that absorb daptomycin before it can target the bacterial membrane. However, this resistance mechanism can be inactivated either by co-treatment with oxacillin or in strains that also secrete phenol-soluble modulins (PSMs), which have surfactant properties and disrupt lipid binding.
References
Müller, A. et al. Daptomycin inhibits cell envelope synthesis by interfering with fluid membrane microdomains. Proc. Natl Acad. Sci. USA http://dx.doi.org/10.1073/pnas.1611173113 (2016)
Pader, V. et al. Staphylococcus aureus inactivates daptomycin by releasing membrane phospholipids. Nat. Microbiol. 2, 16194 (2016)
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Hofer, U. The central role of lipids in daptomycin action. Nat Rev Microbiol 14, 729 (2016). https://doi.org/10.1038/nrmicro.2016.172
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DOI: https://doi.org/10.1038/nrmicro.2016.172