Minor sequence modifications in temporin B cause drastic changes in antibacterial potency and selectivity by fundamentally altering membrane activity

Journal article


Manzo, G, Ferguson, PM, Gustilo, VB, Hind, CK, Clifford, M, Bui, TT, Drake, AF, Atkinson, RA, Sutton, JM, Batoni, G, Lorenz, CD, Phoenix, DA and Mason, AJ (2019). Minor sequence modifications in temporin B cause drastic changes in antibacterial potency and selectivity by fundamentally altering membrane activity. Scientific Reports. 9 (1), p. 1385. https://doi.org/10.1038/s41598-018-37630-3
AuthorsManzo, G, Ferguson, PM, Gustilo, VB, Hind, CK, Clifford, M, Bui, TT, Drake, AF, Atkinson, RA, Sutton, JM, Batoni, G, Lorenz, CD, Phoenix, DA and Mason, AJ
Abstract

Antimicrobial peptides (AMPs) are a potential source of new molecules to counter the increase in antimicrobial resistant infections but a better understanding of their properties is required to understand their native function and for effective translation as therapeutics. Details of the mechanism of their interaction with the bacterial plasma membrane are desired since damage or penetration of this structure is considered essential for AMPs activity. Relatively modest modifications to AMPs primary sequence can induce substantial changes in potency and/or spectrum of activity but, hitherto, have not been predicted to substantially alter the mechanism of interaction with the bacterial plasma membrane. Here we use a combination of molecular dynamics simulations, circular dichroism, solid-state NMR and patch clamp to investigate the extent to which temporin B and its analogues can be distinguished both in vitro and in silico on the basis of their interactions with model membranes. Enhancing the hydrophobicity of the N-terminus and cationicity of the C-terminus in temporin B improves its membrane activity and potency against both Gram-negative and Gram-positive bacteria. In contrast, enhancing the cationicity of the N-terminus abrogates its ability to trigger channel conductance and renders it ineffective against Gram-positive bacteria while nevertheless enhancing its potency against Escherichia coli. Our findings suggest even closely related AMPs may target the same bacterium with fundamentally differing mechanisms of action.

Year2019
JournalScientific Reports
Journal citation9 (1), p. 1385
PublisherNature Research
ISSN2045-2322
Digital Object Identifier (DOI)https://doi.org/10.1038/s41598-018-37630-3
Web address (URL)https://www.nature.com/articles/s41598-018-37630-3
Publication dates
Print04 Feb 2019
Publication process dates
Deposited07 Mar 2019
Accepted10 Dec 2018
Publisher's version
License
File Access Level
Open
Permalink -

https://openresearch.lsbu.ac.uk/item/867vx

Download files


Publisher's version
Phoenix - Minor.pdf
License: CC BY 4.0
File access level: Open

  • 95
    total views
  • 139
    total downloads
  • 5
    views this month
  • 4
    downloads this month

Export as

Related outputs

Bacterial susceptibility and resistance to modelin-5.
Dennison, S., Morton, L. H., Badiani, K., Harris, F. and Phoenix, D. (2023). Bacterial susceptibility and resistance to modelin-5. Soft Matter. 19 (42), pp. 8247-8263. https://doi.org/10.1039/d3sm01007d
Temporin B Forms Hetero-Oligomers with Temporin L, Modifies Its Membrane Activity, and Increases the Cooperativity of Its Antibacterial Pharmacodynamic Profile
Ferguson, Philip M., Clarke, M., Manzo, Giorgia, Hind, Charlotte K., Clifford, Melanie, Sutton, J., Lorenz, C., Phoenix, David A. and Mason, A. (2022). Temporin B Forms Hetero-Oligomers with Temporin L, Modifies Its Membrane Activity, and Increases the Cooperativity of Its Antibacterial Pharmacodynamic Profile. Biochemistry. 61 (11), pp. 1029-1040. https://doi.org/10.1021/acs.biochem.1c00762
PEGylation enhances the antibacterial and therapeutic potential of amphibian host defence peptides.
Dennison, S., Reddy, S.M., Morton, L.H.G., Harris, F., Badiani, K. and Phoenix, D.A (2021). PEGylation enhances the antibacterial and therapeutic potential of amphibian host defence peptides. Biochimica et biophysica acta. Biomembranes. 1864 (1), p. 183806. https://doi.org/10.1016/j.bbamem.2021.183806
Impacts of Metabolism and Organic Acids on Cell Wall Composition and Pseudomonas aeruginosa Susceptibility to Membrane Active Antimicrobials
Manzo, G., Gianfanti, F., Hind, C.K., Allison, L., Clarke, M., Hohenbichler, J., Limantoro, I., Martin, B., Do Carmo Silva, P., Ferguson, P.M., Hodgson-Casson, A., Fleck, R.A., Sutton, J., Phoenix, D.A. and Mason, A. (2021). Impacts of Metabolism and Organic Acids on Cell Wall Composition and Pseudomonas aeruginosa Susceptibility to Membrane Active Antimicrobials. ACS Infectious Diseases. 7 (8), pp. 2310-2323. https://doi.org/10.1021/acsinfecdis.1c00002
Antimicrobial Peptides with pH-Dependent Activity and Alkaline Optima: Their Origins, Mechanisms of Action and Potential Applications
Phoenix, D.A., Harris, F. and Dennison, S. (2021). Antimicrobial Peptides with pH-Dependent Activity and Alkaline Optima: Their Origins, Mechanisms of Action and Potential Applications. Current Protein & Peptide Science. 22 (11), pp. 775-799. https://doi.org/10.2174/1389203722666210728105451
Linearized esculentin-2EM shows pH dependent antibacterial activity with an alkaline optimum.
Malik, E., Phoenix, D., Snape, T.J, Harris, F., Singh, J., Morton, .L.H.G. and Dennison, S. (2021). Linearized esculentin-2EM shows pH dependent antibacterial activity with an alkaline optimum. Molecular and Cellular Biochemistry. https://doi.org/10.1007/s11010-021-04181-7
A pleurocidin analogue with greater conformational flexibility, enhanced antimicrobial potency and in vivo therapeutic efficacy.
Manzo, G., Hind, C.K, Ferguson, P.M, Amison, R.T, Hodgson-Casson, A., Ciazynska, K.A., Weller, B.J, Clarke, M., Lam, C., Man, R.C ., O'Shaughnessy, B.G., Clifford, M., Bui, T., Drake, Alex F, Atkinson, R., Lam, J., Pitchford, S.C, Page, C.P, Phoenix, D.A, Lorenz, C., Sutton, J. and Mason, A. (2020). A pleurocidin analogue with greater conformational flexibility, enhanced antimicrobial potency and in vivo therapeutic efficacy. Communications biology. 3 (1), p. 697. https://doi.org/10.1038/s42003-020-01420-3
Biophysical studies on the antimicrobial activity of linearized esculentin 2EM
Malik, E., Phoenix, D., Badiana, K., Snape, T.J., Harris, F., Singh, J. and Dennison, S. (2019). Biophysical studies on the antimicrobial activity of linearized esculentin 2EM. BBA: Biomembranes. 1862 (2), p. 183141. https://doi.org/10.1016/j.bbamem.2019.183141
Temporin L and aurein 2.5 have identical conformations but subtly distinct membrane and antibacterial activities
Manzo, G., Ferguson, P.M., Hind, C.K., Clifford, M., Gustilo, V.B., Ali, H., Bansal, S.S., Bui, T.T., Drake, A.F., Atkinson, R.A., Sutton, J.M., Lorenz, C.D., Phoenix, D. and Mason, A.J. (2019). Temporin L and aurein 2.5 have identical conformations but subtly distinct membrane and antibacterial activities. Scientific Reports. 9. https://doi.org/10.1038/s41598-019-47327-w
Liposome Mediated-CYP1A1 Gene Silencing Nanomedicine Prepared Using Lipid Film-Coated Proliposomes as a Potential Treatment Strategy of Lung Cancer
Zhang, M, Wang, Q, Wan, K, Ahmed, W, Phoenix, D, Zhang, Z, Elrayess, MA, Elhissi, A and Sun, X (2019). Liposome Mediated-CYP1A1 Gene Silencing Nanomedicine Prepared Using Lipid Film-Coated Proliposomes as a Potential Treatment Strategy of Lung Cancer. International Journal of Pharmaceutics. 566, pp. 185-193. https://doi.org/10.1016/j.ijpharm.2019.04.078
Biophysical investigation into the antibacterial action of modelin-5-NH2
Dennison, S, Hauß, T, Badiani, K, Harris, F and Phoenix, D (2019). Biophysical investigation into the antibacterial action of modelin-5-NH2. Soft Matter. https://doi.org/10.1039/C8SM02374C
The effect of C-terminal amidation on the efficacy and selectivity of antimicrobial and anticancer peptides
Harris, F, Dennison, S, Bhatt, T, Singh, J and Phoenix, DA (2009). The effect of C-terminal amidation on the efficacy and selectivity of antimicrobial and anticancer peptides. Molecular and Cellular Biochemistry. 332 (43). https://doi.org/https://www.doi.org/10.1007/s11010-009-0172-8
Investigation of hydrophobic moment and hydrophobicity properties for transmembrane α-helices
Wallace, J, Daman, OA, Harris, F and Phoenix, DA (2004). Investigation of hydrophobic moment and hydrophobicity properties for transmembrane α-helices. Theoretical Biology and Medical Modelling. 1 (5). https://doi.org/10.1186/1742-4682-1-5
An Atlas of Anionic Antimicrobial Peptides from Amphibians
Dennison, SR, Harris, F, Mura, M and Phoenix, DA (2018). An Atlas of Anionic Antimicrobial Peptides from Amphibians. Current Protein & Peptide Science. 19 (8), pp. 823-838. https://doi.org/10.2174/1389203719666180226155035
Bacterial resistance to host defence peptides
Phoenix, DA, Dennison, SR and Harris, F (2016). Bacterial resistance to host defence peptides. in: Host Defense Peptides and Their Potential as Therapeutic Agents Springer. pp. 161-204
Prediction of Peptide and Protein Propensity for Amyloid Formation
Famlia, C, Dennison, SR, Quintas, A and Phoenix, DA (2015). Prediction of Peptide and Protein Propensity for Amyloid Formation. PLoS ONE. 10. https://doi.org/10.1371/journal.pone.0134679
Investigations into the potential anticancer activity of Maximin H5
Dennison, SR, Harris, F and Phoenix, DA (2017). Investigations into the potential anticancer activity of Maximin H5. Biochimie. 137 (June), pp. 29-34. https://doi.org/10.1016/j.biochi.2017.02.013
The effect of amidation on the behaviour of antimicrobial peptides
Mura, M, Wang, J, Zhou, Y, Pinna, M, Zvelindovsky, A, Dennison, SR and Phoenix, DA (2016). The effect of amidation on the behaviour of antimicrobial peptides. European Biophysics Journal. 45 (3), pp. 195-207. https://doi.org/10.1007/s00249-015-1094-x
Low pH enhances the action of maximin H5 against Staphylococcus aureus and helps mediate lysylated phosphatidylglycerol induced resistance
Dennison, S, Morton, L, Harris, F and Phoenix, DA (2016). Low pH enhances the action of maximin H5 against Staphylococcus aureus and helps mediate lysylated phosphatidylglycerol induced resistance. Biochemistry. 55 (27), pp. 3735-3751. https://doi.org/10.1021/acs.biochem.6b00101
Anionic host defence peptides from the plant kingdom: their anticancer activity and mechanisms of action
Harris, F, Prabhu, S, R Dennison, S, J Snape, T, Lea, R, Mura, M and Phoenix, DA (2016). Anionic host defence peptides from the plant kingdom: their anticancer activity and mechanisms of action. Protein and peptide letters. 23 (8), pp. 676-687. https://doi.org/10.2174/0929866523666160511151215
PH dependent antimicrobial peptides and proteins, their mechanisms of action and potential as therapeutic agents
Malik, E, Dennison, SR, Harris, F and Phoenix, DA (2016). PH dependent antimicrobial peptides and proteins, their mechanisms of action and potential as therapeutic agents. Pharmaceuticals. 9 (4). https://doi.org/10.3390/ph9040067
Ethanol-based proliposome delivery systems of paclitaxel for in vitro application against brain cancer cells
Najlah, M, Jain, M, Wan, KW, Ahmed, W, Albed Alhnan, M, Phoenix, DA, Taylor, KMG and Elhissi, A (2016). Ethanol-based proliposome delivery systems of paclitaxel for in vitro application against brain cancer cells. Journal of Liposome Research. 28 (1), pp. 74-85. https://doi.org/10.1080/08982104.2016.1259628
The role of C-terminal amidation in the membrane interactions of the anionic antimicrobial peptide, maximin H5.
Dennison, SR, Mura, M, Harris, F, Morton, LH, Zvelindovsky, A and Phoenix, DA (2015). The role of C-terminal amidation in the membrane interactions of the anionic antimicrobial peptide, maximin H5. BBA - Biochimica et Biophysica Acta. 1848 (5), pp. 1111 - 1118. https://doi.org/10.1016/j.bbamem.2015.01.014