Coniontins, lipopetaibiotics active against Candida auris identified from a microbial natural product fractionation library
Abstract The rise of drug-resistant fungal pathogens, including Candida auris, highlights the urgent need for innovative antifungal therapies. We have developed a cost-effective platform combining microbial extract prefractionation with rapid mass spectrometry-bioinformatics-based dereplication to e...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62630-z |
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| author | Xuefei Chen Kalinka Koteva Sommer Chou Allison Guitor Daniel Pallant Yunjin Lee David Sychantha Shawn French Dirk Hackenberger Nicole Robbins Michael A. Cook Eric D. Brown Lesley T. MacNeil Leah E. Cowen Gerard D. Wright |
| author_facet | Xuefei Chen Kalinka Koteva Sommer Chou Allison Guitor Daniel Pallant Yunjin Lee David Sychantha Shawn French Dirk Hackenberger Nicole Robbins Michael A. Cook Eric D. Brown Lesley T. MacNeil Leah E. Cowen Gerard D. Wright |
| author_sort | Xuefei Chen |
| collection | DOAJ |
| description | Abstract The rise of drug-resistant fungal pathogens, including Candida auris, highlights the urgent need for innovative antifungal therapies. We have developed a cost-effective platform combining microbial extract prefractionation with rapid mass spectrometry-bioinformatics-based dereplication to efficiently prioritize previously uncharacterized antifungal scaffolds. Screening C. auris and Candida albicans reveals coniotins, lipopeptaibiotics isolated from Coniochaeta hoffmannii, which are undetectable in crude extracts. Coniotins exhibits potent activity against critical priority fungal pathogens listed by the World Health Organization, including C. albicans, Cryptococcus neoformans, multidrug-resistant Candida auris, and Aspergillus fumigatus, with high selectivity and low resistance potential. Coniotin A targets beta-glucan, compromising fungal cell wall integrity, remodelling, and sensitizing C. auris to caspofungin. Identification of its hybrid polyketide synthase–nonribosomal peptide synthetase biosynthetic gene cluster facilitates discovering structurally diverse lipopeptaibiotics. Here, we show that natural product prefractionation enables the discovery of previously hidden bioactive scaffolds and introduces coniotins as candidates for combating multidrug-resistant fungal pathogens. |
| format | Article |
| id | doaj-art-3f77fdd6355440518ebc1d6ef44d5849 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-3f77fdd6355440518ebc1d6ef44d58492025-08-20T03:46:15ZengNature PortfolioNature Communications2041-17232025-08-0116111910.1038/s41467-025-62630-zConiontins, lipopetaibiotics active against Candida auris identified from a microbial natural product fractionation libraryXuefei Chen0Kalinka Koteva1Sommer Chou2Allison Guitor3Daniel Pallant4Yunjin Lee5David Sychantha6Shawn French7Dirk Hackenberger8Nicole Robbins9Michael A. Cook10Eric D. Brown11Lesley T. MacNeil12Leah E. Cowen13Gerard D. Wright14David Braley Centre for Antibiotic Discovery, M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster UniversityDavid Braley Centre for Antibiotic Discovery, M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster UniversityDavid Braley Centre for Antibiotic Discovery, M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster UniversityDavid Braley Centre for Antibiotic Discovery, M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster UniversityDavid Braley Centre for Antibiotic Discovery, M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster UniversityDepartment of Molecular Genetics, University of TorontoDavid Braley Centre for Antibiotic Discovery, M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster UniversityDavid Braley Centre for Antibiotic Discovery, M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster UniversityDavid Braley Centre for Antibiotic Discovery, M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster UniversityDepartment of Molecular Genetics, University of TorontoDavid Braley Centre for Antibiotic Discovery, M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster UniversityDavid Braley Centre for Antibiotic Discovery, M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster UniversityDavid Braley Centre for Antibiotic Discovery, M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster UniversityDepartment of Molecular Genetics, University of TorontoDavid Braley Centre for Antibiotic Discovery, M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster UniversityAbstract The rise of drug-resistant fungal pathogens, including Candida auris, highlights the urgent need for innovative antifungal therapies. We have developed a cost-effective platform combining microbial extract prefractionation with rapid mass spectrometry-bioinformatics-based dereplication to efficiently prioritize previously uncharacterized antifungal scaffolds. Screening C. auris and Candida albicans reveals coniotins, lipopeptaibiotics isolated from Coniochaeta hoffmannii, which are undetectable in crude extracts. Coniotins exhibits potent activity against critical priority fungal pathogens listed by the World Health Organization, including C. albicans, Cryptococcus neoformans, multidrug-resistant Candida auris, and Aspergillus fumigatus, with high selectivity and low resistance potential. Coniotin A targets beta-glucan, compromising fungal cell wall integrity, remodelling, and sensitizing C. auris to caspofungin. Identification of its hybrid polyketide synthase–nonribosomal peptide synthetase biosynthetic gene cluster facilitates discovering structurally diverse lipopeptaibiotics. Here, we show that natural product prefractionation enables the discovery of previously hidden bioactive scaffolds and introduces coniotins as candidates for combating multidrug-resistant fungal pathogens.https://doi.org/10.1038/s41467-025-62630-z |
| spellingShingle | Xuefei Chen Kalinka Koteva Sommer Chou Allison Guitor Daniel Pallant Yunjin Lee David Sychantha Shawn French Dirk Hackenberger Nicole Robbins Michael A. Cook Eric D. Brown Lesley T. MacNeil Leah E. Cowen Gerard D. Wright Coniontins, lipopetaibiotics active against Candida auris identified from a microbial natural product fractionation library Nature Communications |
| title | Coniontins, lipopetaibiotics active against Candida auris identified from a microbial natural product fractionation library |
| title_full | Coniontins, lipopetaibiotics active against Candida auris identified from a microbial natural product fractionation library |
| title_fullStr | Coniontins, lipopetaibiotics active against Candida auris identified from a microbial natural product fractionation library |
| title_full_unstemmed | Coniontins, lipopetaibiotics active against Candida auris identified from a microbial natural product fractionation library |
| title_short | Coniontins, lipopetaibiotics active against Candida auris identified from a microbial natural product fractionation library |
| title_sort | coniontins lipopetaibiotics active against candida auris identified from a microbial natural product fractionation library |
| url | https://doi.org/10.1038/s41467-025-62630-z |
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