A pleurocidin analogue with greater conformational flexibility, enhanced antimicrobial potency and in vivo therapeutic efficacy.

Journal article


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
AuthorsManzo, 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.
AbstractAntimicrobial peptides (AMPs) are a potential alternative to classical antibiotics that are yet to achieve a therapeutic breakthrough for treatment of systemic infections. The antibacterial potency of pleurocidin, an AMP from Winter Flounder, is linked to its ability to cross bacterial plasma membranes and seek intracellular targets while also causing membrane damage. Here we describe modification strategies that generate pleurocidin analogues with substantially improved, broad spectrum, antibacterial properties, which are effective in murine models of bacterial lung infection. Increasing peptide-lipid intermolecular hydrogen bonding capabilities enhances conformational flexibility, associated with membrane translocation, but also membrane damage and potency, most notably against Gram-positive bacteria. This negates their ability to metabolically adapt to the AMP threat. An analogue comprising D-amino acids was well tolerated at an intravenous dose of 15 mg/kg and similarly effective as vancomycin in reducing EMRSA-15 lung CFU. This highlights the therapeutic potential of systemically delivered, bactericidal AMPs.
Year2020
JournalCommunications biology
Journal citation3 (1), p. 697
PublisherSpringer
ISSN2399-3642
Digital Object Identifier (DOI)https://doi.org/10.1038/s42003-020-01420-3
Funder/ClientWellcome Trust
Publication dates
Online27 Nov 2020
Publication process dates
Accepted22 Oct 2020
Deposited15 Dec 2020
Publisher's version
License
File Access Level
Open
Permalink -

https://openresearch.lsbu.ac.uk/item/8vq25

Download files


Publisher's version
s42003-020-01420-3.pdf
License: CC BY 4.0
File access level: Open

  • 14
    total views
  • 20
    total downloads
  • 0
    views this month
  • 0
    downloads this month

Export as

Related outputs

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.R. (2021). Antimicrobial peptides with pH dependent activity and alkaline optima: their origins, mechanisms of action and potential applications. Current Protein & Peptide Science. 22. 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
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
Minor sequence modifications in temporin B cause drastic changes in antibacterial potency and selectivity by fundamentally altering membrane activity
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
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 International Publishing. 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