Expanding the toolbox for the study of antimicrobial peptides
There is an urgent lack of new antibiotics in the face of an ever-expanding antimicrobial resistance crisis. The fact that fewer new classes of antibiotics are being developed, and resistance soon follows newly available antibiotics, only serves to underline the urgency of the matter. There is a cle...
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Format: | Doctoral or Postdoctoral Thesis |
Language: | English |
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UiT Norges arktiske universitet
2022
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Online Access: | https://hdl.handle.net/10037/25236 |
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Open Polar |
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University of Tromsø: Munin Open Research Archive |
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ftunivtroemsoe |
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English |
topic |
VDP::Mathematics and natural science: 400::Chemistry: 440::Analytical chemistry: 445 VDP::Matematikk og Naturvitenskap: 400::Kjemi: 440::Analytisk kjemi: 445 DOKTOR-004 |
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VDP::Mathematics and natural science: 400::Chemistry: 440::Analytical chemistry: 445 VDP::Matematikk og Naturvitenskap: 400::Kjemi: 440::Analytisk kjemi: 445 DOKTOR-004 Rainsford, Philip Expanding the toolbox for the study of antimicrobial peptides |
topic_facet |
VDP::Mathematics and natural science: 400::Chemistry: 440::Analytical chemistry: 445 VDP::Matematikk og Naturvitenskap: 400::Kjemi: 440::Analytisk kjemi: 445 DOKTOR-004 |
description |
There is an urgent lack of new antibiotics in the face of an ever-expanding antimicrobial resistance crisis. The fact that fewer new classes of antibiotics are being developed, and resistance soon follows newly available antibiotics, only serves to underline the urgency of the matter. There is a clear need of a paradigm shift with regards to antibiotics, and one such hope is antimicrobial peptides (AMPs). AMPs are an integral part of the innate immune systems of most organisms within the domains of life; since their discovery they have become of significant interest as a new type of antimicrobial agent, due in part to the low capacity of bacteria to develop resistance mechanisms towards them. Despite their potential, and lengthy study so far, establishing the specifics of the mechanism of action of many AMPs remains difficult– particularly of those that target the bacterial cell membrane. This lack of understanding limits the ability to rationally design new AMPs with a view to developing new antimicrobial agents. The aim of this work was to help identify new potential hit compounds through NMR structure elucidation, and to develop new methods that would give greater insight into the activity of membrane active AMPs. This in turn could help enable the rational design of new AMPs. WIND-PVPA, a method to quantify permeabilities of water and ions as a means to evaluate the disruptive capabilities of AMPs, was developed. This was demonstrated on a number of AMPs, and it was shown that WIND-PVPA can identify AMPs that have strong, selective, membrane disruptive activities such as the AMP WRWRWR, as well as more modestly disruptive AMPs such as KP-76. The WIND-PVPA was further used with a non-AMP membrane active natural product – lulworthinone – that was characterised over the course of the project. The findings of the study helped classify lulworthinone as a non-disruptive membrane active agent. In addition, microscale thermophoresis (MST) was shown to be a viable method by which the binding and partition ... |
format |
Doctoral or Postdoctoral Thesis |
author |
Rainsford, Philip |
author_facet |
Rainsford, Philip |
author_sort |
Rainsford, Philip |
title |
Expanding the toolbox for the study of antimicrobial peptides |
title_short |
Expanding the toolbox for the study of antimicrobial peptides |
title_full |
Expanding the toolbox for the study of antimicrobial peptides |
title_fullStr |
Expanding the toolbox for the study of antimicrobial peptides |
title_full_unstemmed |
Expanding the toolbox for the study of antimicrobial peptides |
title_sort |
expanding the toolbox for the study of antimicrobial peptides |
publisher |
UiT Norges arktiske universitet |
publishDate |
2022 |
url |
https://hdl.handle.net/10037/25236 |
genre |
Arctic |
genre_facet |
Arctic |
op_relation |
Paper I: Rainsford, P., Sarre, R., Falavigna, M., Brandsdal, B.O., Flaten, G.E., Jakubec, M. & Isaksson, J. (2022). WIND-PVPA: Water/Ion NMR Detected PVPA to assess lipid barrier integrity in vitro through quantification of passive water- and ion transport. Biochimica et Biophysica Acta (BBA) – Biomembranes, 1864 (7), 1839112022. Also available in Munin at https://hdl.handle.net/10037/25229 . Paper II: Rainsford, P., Jakubec, M., Silk, M., Engh, R. & Isaksson, J. Novel application of label free MST: Measurement of AMP affinity (KD) and partitioning (KP) to lipid vesicles and SMA-lipid nanodiscs. (Manuscript). Paper III: Jenssen, M., Rainsford, P., Juskewitz, E., Andersen, J.H., Hansen, E.H., Isaksson, J., Rämä, T. & Hansen, K.Ø. (2021). Lulworthinone, a New Dimeric Naphthopyrone From a Marine Fungus in the Family Lulworthiaceae With Antibacterial Activity Against Clinical Methicillin-Resistant Staphylococcus aureus Isolates. Frontiers in Microbiology, 12 , 730740. Also available in Munin at https://hdl.handle.net/10037/22945 . Paper IV: Juskewitz, E., Mishchenko, E., Dubey, V.K., Jenssen, M., Jakubec, M., Rainsford, P., … Ericson, J.U. Lulworthinone: In vitro mode of action investigation of an antibacterial dimeric naphthopyrone isolated from a marine fungus. (Submitted manuscript). Now published in Marine Drugs, 20 (5), 277, available at https://doi.org/10.3390/md20050277 . Paper V: Hansen, I.K.Ø., Rainsford, P.B., Isaksson, J., Hansen, K.Ø., Stensvåg, K., Albert, A., Vasskog, T. & Haug, T. Isolation and characterization of St-CRPs: Cysteine-rich peptides from the Arctic marine ascidian Synoicum turgens . (Manuscript). 978-82-8236-480-5 https://hdl.handle.net/10037/25236 |
op_rights |
openAccess Copyright 2022 The Author(s) |
_version_ |
1766302405235834880 |
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ftunivtroemsoe:oai:munin.uit.no:10037/25236 2023-05-15T14:28:14+02:00 Expanding the toolbox for the study of antimicrobial peptides Rainsford, Philip 2022-06-02 https://hdl.handle.net/10037/25236 eng eng UiT Norges arktiske universitet UiT The Arctic University of Norway Paper I: Rainsford, P., Sarre, R., Falavigna, M., Brandsdal, B.O., Flaten, G.E., Jakubec, M. & Isaksson, J. (2022). WIND-PVPA: Water/Ion NMR Detected PVPA to assess lipid barrier integrity in vitro through quantification of passive water- and ion transport. Biochimica et Biophysica Acta (BBA) – Biomembranes, 1864 (7), 1839112022. Also available in Munin at https://hdl.handle.net/10037/25229 . Paper II: Rainsford, P., Jakubec, M., Silk, M., Engh, R. & Isaksson, J. Novel application of label free MST: Measurement of AMP affinity (KD) and partitioning (KP) to lipid vesicles and SMA-lipid nanodiscs. (Manuscript). Paper III: Jenssen, M., Rainsford, P., Juskewitz, E., Andersen, J.H., Hansen, E.H., Isaksson, J., Rämä, T. & Hansen, K.Ø. (2021). Lulworthinone, a New Dimeric Naphthopyrone From a Marine Fungus in the Family Lulworthiaceae With Antibacterial Activity Against Clinical Methicillin-Resistant Staphylococcus aureus Isolates. Frontiers in Microbiology, 12 , 730740. Also available in Munin at https://hdl.handle.net/10037/22945 . Paper IV: Juskewitz, E., Mishchenko, E., Dubey, V.K., Jenssen, M., Jakubec, M., Rainsford, P., … Ericson, J.U. Lulworthinone: In vitro mode of action investigation of an antibacterial dimeric naphthopyrone isolated from a marine fungus. (Submitted manuscript). Now published in Marine Drugs, 20 (5), 277, available at https://doi.org/10.3390/md20050277 . Paper V: Hansen, I.K.Ø., Rainsford, P.B., Isaksson, J., Hansen, K.Ø., Stensvåg, K., Albert, A., Vasskog, T. & Haug, T. Isolation and characterization of St-CRPs: Cysteine-rich peptides from the Arctic marine ascidian Synoicum turgens . (Manuscript). 978-82-8236-480-5 https://hdl.handle.net/10037/25236 openAccess Copyright 2022 The Author(s) VDP::Mathematics and natural science: 400::Chemistry: 440::Analytical chemistry: 445 VDP::Matematikk og Naturvitenskap: 400::Kjemi: 440::Analytisk kjemi: 445 DOKTOR-004 Doctoral thesis Doktorgradsavhandling 2022 ftunivtroemsoe 2022-05-25T22:58:56Z There is an urgent lack of new antibiotics in the face of an ever-expanding antimicrobial resistance crisis. The fact that fewer new classes of antibiotics are being developed, and resistance soon follows newly available antibiotics, only serves to underline the urgency of the matter. There is a clear need of a paradigm shift with regards to antibiotics, and one such hope is antimicrobial peptides (AMPs). AMPs are an integral part of the innate immune systems of most organisms within the domains of life; since their discovery they have become of significant interest as a new type of antimicrobial agent, due in part to the low capacity of bacteria to develop resistance mechanisms towards them. Despite their potential, and lengthy study so far, establishing the specifics of the mechanism of action of many AMPs remains difficult– particularly of those that target the bacterial cell membrane. This lack of understanding limits the ability to rationally design new AMPs with a view to developing new antimicrobial agents. The aim of this work was to help identify new potential hit compounds through NMR structure elucidation, and to develop new methods that would give greater insight into the activity of membrane active AMPs. This in turn could help enable the rational design of new AMPs. WIND-PVPA, a method to quantify permeabilities of water and ions as a means to evaluate the disruptive capabilities of AMPs, was developed. This was demonstrated on a number of AMPs, and it was shown that WIND-PVPA can identify AMPs that have strong, selective, membrane disruptive activities such as the AMP WRWRWR, as well as more modestly disruptive AMPs such as KP-76. The WIND-PVPA was further used with a non-AMP membrane active natural product – lulworthinone – that was characterised over the course of the project. The findings of the study helped classify lulworthinone as a non-disruptive membrane active agent. In addition, microscale thermophoresis (MST) was shown to be a viable method by which the binding and partition ... Doctoral or Postdoctoral Thesis Arctic University of Tromsø: Munin Open Research Archive |