The Antibiotic Peptide Daptomycin Functions by Reorganizing the Membrane

Abstract

The mechanism of the antimicrobial peptide daptomycin is reviewed and discussed. Daptomycin is a last-resort antibiotic in current use against drug-resistant bacterial infections. Many models have been proposed for its function, most based on the observation that it increases membrane permeability and causes leakage of contents, such as ions and small molecules from bacterial cells and lipid vesicles. However, daptomycin is actually not efficient at permeabilizing or translocating across membranes, contrary to many well-known antimicrobial peptides. There is strong evidence that daptomycin binds preferentially to membranes in active division regions of bacterial cells and that it causes large membrane reorganization in terms of the distribution of lipids and proteins, both in cells and in model membranes. Those observations support the alternative hypothesis for the mechanism of daptomycin that its primary effect is in inducing membrane reorganization and that other events, such as increased membrane leakage and depolarization, are secondary consequences, not essential to its function.

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Fig. 1
Fig. 2

Reprinted with permission from Pokorny, A., Khatib, T.O., and Stevenson, H. J. Phys. Chem. B 2018, 122, 9137–9146, Copyright ©2018 American Chemical Society (Color figure online)

Fig. 3

Reprinted with permission from Kreutzberger, M.A., Pokorny, A., and Almeida, P.F. Langmuir 2017, 33, 13669–13679, Copyright ©2017 American Chemical Society

Fig. 4

Reprinted with permission from Jung, D., Rozek, A., Okon, M., and Hancock, R.E.W. Chem. Biol. 2004, 11, 949–957, Copyright ©2004 Elsevier

Fig. 5

a, b Reprinted with permission from Kreutzberger, M.A., Pokorny, A., and Almeida, P.F. Langmuir 2017, 33, 13669–13679, Copyright ©2017 American Chemical Society. c Reprinted with permission from Wheaten, S.A., Ablan, F.D.O., Spaller, B.L., Trieu, J.M., and Almeida, P.F. J. Am. Chem. Soc. 2013, 135, 16517–16525, Copyright ©2013 American Chemical Society

Fig. 6

Reprinted with permission from Kreutzberger, M.A., Pokorny, A., and Almeida, P.F. Langmuir 2017, 33, 13669–13679, Copyright ©2017 American Chemical Society (Color figure online)

Fig. 7

Left, Reprinted with permission from Pogliano, J., Pogliano, N., and Silverman, J.A. J. Bacteriol. 2012, 194, 4494–4504, https://doi.org/10.1128/JB.00011-12, Copyright ©2012, American Society for Microbiology. Right, Reprinted with permission from Grein, F., Müller, A., Scherer, K.M., Liu, X., Ludwig, K.C., Klöckner, A., Strach, M., Sahl, H.G., Kubitscheck, U., and Schneider, T. Nat. Commun. 2020, 11, 1455, Copyright ©2020, The Authors (Color figure online)

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Acknowledgements

We would like to thank Steve White for many years of discussions—and for many disagreements. For it is through disagreement that science progresses. Most of all, we have always valued Steve’s drive to get to the bottom of the questions and to understand the problems, not being satisfied with half-answers. His contributions have made making science a lot more interesting and stimulating.

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Correspondence to Paulo F. Almeida.

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Pokorny, A., Almeida, P.F. The Antibiotic Peptide Daptomycin Functions by Reorganizing the Membrane. J Membrane Biol 254, 97–108 (2021). https://doi.org/10.1007/s00232-021-00175-0

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Keywords

  • Antimicrobial peptide
  • Lipid domains
  • Membrane reorganization