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P003 Synthetic antifungal peptide mimic kills Candida albicans by targeting protein glycosylation and synergistically prevents infection

POSTER SESSION 1, SEPTEMBER 21, 2022, 12:30 PM - 1:30 PM: Fungal infections represent a serious burden on human health. Increasing numbers of susceptible hosts, a limited set of approved antifungal drugs which frequently trigger undesired side effects, and the emergence of resistant strains highligh...

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Autores principales: Schaefer, Sebastian, Vij, Raghav, Sprague, Jakob, Seemann, Eric, Hube, Bernhard, Lenardon, Megan, Boyer, Cyrille, Brunke, Sascha
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9509771/
http://dx.doi.org/10.1093/mmy/myac072.P003
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author Schaefer, Sebastian
Vij, Raghav
Sprague, Jakob
Seemann, Eric
Hube, Bernhard
Lenardon, Megan
Boyer, Cyrille
Brunke, Sascha
author_facet Schaefer, Sebastian
Vij, Raghav
Sprague, Jakob
Seemann, Eric
Hube, Bernhard
Lenardon, Megan
Boyer, Cyrille
Brunke, Sascha
author_sort Schaefer, Sebastian
collection PubMed
description POSTER SESSION 1, SEPTEMBER 21, 2022, 12:30 PM - 1:30 PM: Fungal infections represent a serious burden on human health. Increasing numbers of susceptible hosts, a limited set of approved antifungal drugs which frequently trigger undesired side effects, and the emergence of resistant strains highlight the urgent demand for novel antifungal drug formulations. However, the biological similarity of human and fungal cells hampers the development of new antifungals which do not also harm humans. In nature, organisms in almost all domains of life produce antimicrobial peptides to combat microbial pathogens. Those peptides share certain characteristics, such as being short, amphiphilic molecules with a positive net charge.(1)  : We designed synthetic polyacrylamides which mimic the properties of naturally occurring antifungal peptides. These positively charged, amphiphilic polymers are advantageous over peptides because of their easy synthesis and stability against proteases. Initial structure-activity relationship studies revealed an optimal cLogP (the calculated hydrophobicity of a molecule) around 1.5 to ensure activity against C. albicans and simultaneous biocompatibility with host cells.(2) Additionally, shorter polymers with a length of 20 subunits were more effective than their longer versions.(2) In terms of their therapeutic index, certain compositions outperformed the broad-spectrum antifungal amphotericin B and were even effective against drug-resistant clinical isolates of C. albicans.(2)  : Candida albicans strains with known antifungal drug-resistance mutations were not affected in their susceptibility to the polymers. Therefore, investigations were carried out to elucidate the mode of action of the polymers. The transcriptome of C. albicans cells treated with subinhibitory concentrations of the polymers revealed an increased expression of genes involved in general stress response and upregulation in protein processing in the endoplasmic reticulum, particularly glycosylation and degradation. These findings, together with electron microscopy observations, indicated damage to the mannoproteins in the cell wall of the fungus. Membrane damage was also observed utilizing a C. albicans strain expressing GFP intracellularly.  : The in vitro therapeutic potential of the most promising polymer was tested in a human epithelial cell (HEC) model simulating C. albicans infection. The polymer alone was not able to prevent C. albicans infection of HECs. However, the combination of polymer with caspofungin or fluconazole showed very strong synergistic effects at otherwise non-inhibitory concentrations of the individual antifungals, successfully stopping fungal infection in vitro without damaging the HECs.  : These results underline the potential of synthetic polymers as an alternative treatment for fungal infections with low toxicity to human cells and a novel mode of action. SOURCES: 1. Fernández de Ullivarri, M., Arbulu, S., Garcia-Gutierrez, E. and Cotter, P.D. Antifungal peptides as therapeutic agents. Front Cell Infect Microbiol 10, 00 105 (2020). 2. Schaefer, S. et al. Rational design of an antifungal polyacrylamide library with reduced host-cell toxicity. ACS Appl Mater Interfaces 13, 27430-27444 (2021).
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spelling pubmed-95097712022-09-26 P003 Synthetic antifungal peptide mimic kills Candida albicans by targeting protein glycosylation and synergistically prevents infection Schaefer, Sebastian Vij, Raghav Sprague, Jakob Seemann, Eric Hube, Bernhard Lenardon, Megan Boyer, Cyrille Brunke, Sascha Med Mycol Oral Presentations POSTER SESSION 1, SEPTEMBER 21, 2022, 12:30 PM - 1:30 PM: Fungal infections represent a serious burden on human health. Increasing numbers of susceptible hosts, a limited set of approved antifungal drugs which frequently trigger undesired side effects, and the emergence of resistant strains highlight the urgent demand for novel antifungal drug formulations. However, the biological similarity of human and fungal cells hampers the development of new antifungals which do not also harm humans. In nature, organisms in almost all domains of life produce antimicrobial peptides to combat microbial pathogens. Those peptides share certain characteristics, such as being short, amphiphilic molecules with a positive net charge.(1)  : We designed synthetic polyacrylamides which mimic the properties of naturally occurring antifungal peptides. These positively charged, amphiphilic polymers are advantageous over peptides because of their easy synthesis and stability against proteases. Initial structure-activity relationship studies revealed an optimal cLogP (the calculated hydrophobicity of a molecule) around 1.5 to ensure activity against C. albicans and simultaneous biocompatibility with host cells.(2) Additionally, shorter polymers with a length of 20 subunits were more effective than their longer versions.(2) In terms of their therapeutic index, certain compositions outperformed the broad-spectrum antifungal amphotericin B and were even effective against drug-resistant clinical isolates of C. albicans.(2)  : Candida albicans strains with known antifungal drug-resistance mutations were not affected in their susceptibility to the polymers. Therefore, investigations were carried out to elucidate the mode of action of the polymers. The transcriptome of C. albicans cells treated with subinhibitory concentrations of the polymers revealed an increased expression of genes involved in general stress response and upregulation in protein processing in the endoplasmic reticulum, particularly glycosylation and degradation. These findings, together with electron microscopy observations, indicated damage to the mannoproteins in the cell wall of the fungus. Membrane damage was also observed utilizing a C. albicans strain expressing GFP intracellularly.  : The in vitro therapeutic potential of the most promising polymer was tested in a human epithelial cell (HEC) model simulating C. albicans infection. The polymer alone was not able to prevent C. albicans infection of HECs. However, the combination of polymer with caspofungin or fluconazole showed very strong synergistic effects at otherwise non-inhibitory concentrations of the individual antifungals, successfully stopping fungal infection in vitro without damaging the HECs.  : These results underline the potential of synthetic polymers as an alternative treatment for fungal infections with low toxicity to human cells and a novel mode of action. SOURCES: 1. Fernández de Ullivarri, M., Arbulu, S., Garcia-Gutierrez, E. and Cotter, P.D. Antifungal peptides as therapeutic agents. Front Cell Infect Microbiol 10, 00 105 (2020). 2. Schaefer, S. et al. Rational design of an antifungal polyacrylamide library with reduced host-cell toxicity. ACS Appl Mater Interfaces 13, 27430-27444 (2021). Oxford University Press 2022-09-20 /pmc/articles/PMC9509771/ http://dx.doi.org/10.1093/mmy/myac072.P003 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Oral Presentations
Schaefer, Sebastian
Vij, Raghav
Sprague, Jakob
Seemann, Eric
Hube, Bernhard
Lenardon, Megan
Boyer, Cyrille
Brunke, Sascha
P003 Synthetic antifungal peptide mimic kills Candida albicans by targeting protein glycosylation and synergistically prevents infection
title P003 Synthetic antifungal peptide mimic kills Candida albicans by targeting protein glycosylation and synergistically prevents infection
title_full P003 Synthetic antifungal peptide mimic kills Candida albicans by targeting protein glycosylation and synergistically prevents infection
title_fullStr P003 Synthetic antifungal peptide mimic kills Candida albicans by targeting protein glycosylation and synergistically prevents infection
title_full_unstemmed P003 Synthetic antifungal peptide mimic kills Candida albicans by targeting protein glycosylation and synergistically prevents infection
title_short P003 Synthetic antifungal peptide mimic kills Candida albicans by targeting protein glycosylation and synergistically prevents infection
title_sort p003 synthetic antifungal peptide mimic kills candida albicans by targeting protein glycosylation and synergistically prevents infection
topic Oral Presentations
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9509771/
http://dx.doi.org/10.1093/mmy/myac072.P003
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