Evaluation of proline-rich antimicrobial peptides as potential lead structures for novel antimycotics against Cryptococcus neoformans
BackgroundCryptococcosis and cryptococcal meningitis, caused by Cryptococcus neoformans infections, lead to approximately 180,000 deaths per year, primarily in developing countries. Individuals with compromised immune systems, e.g., due to HIV infection (AIDS) or chemotherapy, are particularly vulne...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-01-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2023.1328890/full |
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| author | Alexandra Brakel Alexandra Brakel Thomas Grochow Stefanie Fritsche Stefanie Fritsche Daniel Knappe Daniel Knappe Andor Krizsan Andor Krizsan Simone A. Fietz Gottfried Alber Gottfried Alber Ralf Hoffmann Ralf Hoffmann Uwe Müller Uwe Müller |
| author_facet | Alexandra Brakel Alexandra Brakel Thomas Grochow Stefanie Fritsche Stefanie Fritsche Daniel Knappe Daniel Knappe Andor Krizsan Andor Krizsan Simone A. Fietz Gottfried Alber Gottfried Alber Ralf Hoffmann Ralf Hoffmann Uwe Müller Uwe Müller |
| author_sort | Alexandra Brakel |
| collection | DOAJ |
| description | BackgroundCryptococcosis and cryptococcal meningitis, caused by Cryptococcus neoformans infections, lead to approximately 180,000 deaths per year, primarily in developing countries. Individuals with compromised immune systems, e.g., due to HIV infection (AIDS) or chemotherapy, are particularly vulnerable. Conventional treatment options are often limited and can cause severe side effects. Therefore, this study aimed to investigate the antifungal effect of insect-derived proline-rich antimicrobial peptides (PrAMPs) against C. neoformans. These peptides are known for their low toxicity and their high efficacy in murine infection models, making them a promising alternative for treatment.ResultsA preliminary screening of the minimal inhibitory concentrations (MICs) of 20 AMPs, including the well-known PrAMPs Onc112, Api137, and Chex1Arg20 as well as the cathelicidin CRAMP against the C. neoformans strains 1841, H99, and KN99α revealed promising results, with MICs as low as 1.6 μmol/L. Subsequent investigations of selected peptides, determining their influence on fungal colony-forming units, confirmed their strong activity. The antifungal activity was affected by factors such as peptide net charge and sequence, with stronger effects at higher net charges probably due to better intracellular uptake confirmed by confocal laser scanning microscopy. Inactive scrambled peptides suggest a specific intracellular target, although scanning electron microscopy showed that PrAMPs also damaged the cell exterior for a low proportion of the cells. Possible pore formation could facilitate entry into the cytosol. |
| first_indexed | 2024-03-08T16:06:31Z |
| format | Article |
| id | doaj.art-8215278527a84e1cb030a9085e9ff7f1 |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-03-08T16:06:31Z |
| publishDate | 2024-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-8215278527a84e1cb030a9085e9ff7f12024-01-08T05:40:11ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2024-01-011410.3389/fmicb.2023.13288901328890Evaluation of proline-rich antimicrobial peptides as potential lead structures for novel antimycotics against Cryptococcus neoformansAlexandra Brakel0Alexandra Brakel1Thomas Grochow2Stefanie Fritsche3Stefanie Fritsche4Daniel Knappe5Daniel Knappe6Andor Krizsan7Andor Krizsan8Simone A. Fietz9Gottfried Alber10Gottfried Alber11Ralf Hoffmann12Ralf Hoffmann13Uwe Müller14Uwe Müller15Institute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Bioanalytical Chemistry, Leipzig University, Leipzig, GermanyCenter for Biotechnology and Biomedicine, Leipzig University, Leipzig, GermanyInstitute of Veterinary Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, Leipzig University, Leipzig, GermanyCenter for Biotechnology and Biomedicine, Leipzig University, Leipzig, GermanyInstitute of Immunology/Molecular Pathogenesis, Faculty of Veterinary Medicine, Leipzig University, Leipzig, GermanyInstitute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Bioanalytical Chemistry, Leipzig University, Leipzig, GermanyCenter for Biotechnology and Biomedicine, Leipzig University, Leipzig, GermanyInstitute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Bioanalytical Chemistry, Leipzig University, Leipzig, GermanyCenter for Biotechnology and Biomedicine, Leipzig University, Leipzig, GermanyInstitute of Veterinary Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, Leipzig University, Leipzig, GermanyCenter for Biotechnology and Biomedicine, Leipzig University, Leipzig, GermanyInstitute of Immunology/Molecular Pathogenesis, Faculty of Veterinary Medicine, Leipzig University, Leipzig, GermanyInstitute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Bioanalytical Chemistry, Leipzig University, Leipzig, GermanyCenter for Biotechnology and Biomedicine, Leipzig University, Leipzig, GermanyCenter for Biotechnology and Biomedicine, Leipzig University, Leipzig, GermanyInstitute of Immunology/Molecular Pathogenesis, Faculty of Veterinary Medicine, Leipzig University, Leipzig, GermanyBackgroundCryptococcosis and cryptococcal meningitis, caused by Cryptococcus neoformans infections, lead to approximately 180,000 deaths per year, primarily in developing countries. Individuals with compromised immune systems, e.g., due to HIV infection (AIDS) or chemotherapy, are particularly vulnerable. Conventional treatment options are often limited and can cause severe side effects. Therefore, this study aimed to investigate the antifungal effect of insect-derived proline-rich antimicrobial peptides (PrAMPs) against C. neoformans. These peptides are known for their low toxicity and their high efficacy in murine infection models, making them a promising alternative for treatment.ResultsA preliminary screening of the minimal inhibitory concentrations (MICs) of 20 AMPs, including the well-known PrAMPs Onc112, Api137, and Chex1Arg20 as well as the cathelicidin CRAMP against the C. neoformans strains 1841, H99, and KN99α revealed promising results, with MICs as low as 1.6 μmol/L. Subsequent investigations of selected peptides, determining their influence on fungal colony-forming units, confirmed their strong activity. The antifungal activity was affected by factors such as peptide net charge and sequence, with stronger effects at higher net charges probably due to better intracellular uptake confirmed by confocal laser scanning microscopy. Inactive scrambled peptides suggest a specific intracellular target, although scanning electron microscopy showed that PrAMPs also damaged the cell exterior for a low proportion of the cells. Possible pore formation could facilitate entry into the cytosol.https://www.frontiersin.org/articles/10.3389/fmicb.2023.1328890/fullantifungal peptidefungal pathogenintracellular mode-of-actionproline-rich antimicrobial peptide (PrAMP)scanning electron microscopy |
| spellingShingle | Alexandra Brakel Alexandra Brakel Thomas Grochow Stefanie Fritsche Stefanie Fritsche Daniel Knappe Daniel Knappe Andor Krizsan Andor Krizsan Simone A. Fietz Gottfried Alber Gottfried Alber Ralf Hoffmann Ralf Hoffmann Uwe Müller Uwe Müller Evaluation of proline-rich antimicrobial peptides as potential lead structures for novel antimycotics against Cryptococcus neoformans Frontiers in Microbiology antifungal peptide fungal pathogen intracellular mode-of-action proline-rich antimicrobial peptide (PrAMP) scanning electron microscopy |
| title | Evaluation of proline-rich antimicrobial peptides as potential lead structures for novel antimycotics against Cryptococcus neoformans |
| title_full | Evaluation of proline-rich antimicrobial peptides as potential lead structures for novel antimycotics against Cryptococcus neoformans |
| title_fullStr | Evaluation of proline-rich antimicrobial peptides as potential lead structures for novel antimycotics against Cryptococcus neoformans |
| title_full_unstemmed | Evaluation of proline-rich antimicrobial peptides as potential lead structures for novel antimycotics against Cryptococcus neoformans |
| title_short | Evaluation of proline-rich antimicrobial peptides as potential lead structures for novel antimycotics against Cryptococcus neoformans |
| title_sort | evaluation of proline rich antimicrobial peptides as potential lead structures for novel antimycotics against cryptococcus neoformans |
| topic | antifungal peptide fungal pathogen intracellular mode-of-action proline-rich antimicrobial peptide (PrAMP) scanning electron microscopy |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2023.1328890/full |
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