Chemical Genomics-Based Antifungal Drug Discovery: Targeting Glycosylphosphatidylinositol (GPI) Precursor Biosynthesis
Steadily increasing antifungal drug resistance and persistent high rates of fungal-associated mortality highlight the dire need for the development of novel antifungals. Characterization of inhibitors of one enzyme in the GPI anchor pathway, Gwt1, has generated interest in the exploration of targets...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
American Chemical Society (ACS)
2016
|
| Online Access: | http://hdl.handle.net/1721.1/105537 https://orcid.org/0000-0003-1307-882X |
| _version_ | 1826205757889052672 |
|---|---|
| author | Mann, Paul A. Koseoglu, Sandra Si, Qian Kuzmin, Elena Flattery, Amy Harris, Guy Sher, Xinwei Murgolo, Nicholas Wang, Hao Devito, Kristine de Pedro, Nuria Genilloud, Olga Kahn, Jennifer Nielsen Jiang, Bo Costanzo, Michael Boone, Charlie Garlisi, Charles G. Roemer, Terry McLellan, Catherine Lindquist, Susan |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Mann, Paul A. Koseoglu, Sandra Si, Qian Kuzmin, Elena Flattery, Amy Harris, Guy Sher, Xinwei Murgolo, Nicholas Wang, Hao Devito, Kristine de Pedro, Nuria Genilloud, Olga Kahn, Jennifer Nielsen Jiang, Bo Costanzo, Michael Boone, Charlie Garlisi, Charles G. Roemer, Terry McLellan, Catherine Lindquist, Susan |
| author_sort | Mann, Paul A. |
| collection | MIT |
| description | Steadily increasing antifungal drug resistance and persistent high rates of fungal-associated mortality highlight the dire need for the development of novel antifungals. Characterization of inhibitors of one enzyme in the GPI anchor pathway, Gwt1, has generated interest in the exploration of targets in this pathway for further study. Utilizing a chemical genomics-based screening platform referred to as the Candida albicans fitness test (CaFT), we have identified novel inhibitors of Gwt1 and a second enzyme in the glycosylphosphatidylinositol (GPI) cell wall anchor pathway, Mcd4. We further validate these targets using the model fungal organism Saccharomyces cerevisiae and demonstrate the utility of using the facile toolbox that has been compiled in this species to further explore target specific biology. Using these compounds as probes, we demonstrate that inhibition of Mcd4 as well as Gwt1 blocks the growth of a broad spectrum of fungal pathogens and exposes key elicitors of pathogen recognition. Interestingly, a strong chemical synergy is also observed by combining Gwt1 and Mcd4 inhibitors, mirroring the demonstrated synthetic lethality of combining conditional mutants of GWT1 and MCD4. We further demonstrate that the Mcd4 inhibitor M720 is efficacious in a murine infection model of systemic candidiasis. Our results establish Mcd4 as a promising antifungal target and confirm the GPI cell wall anchor synthesis pathway as a promising antifungal target area by demonstrating that effects of inhibiting it are more general than previously recognized. |
| first_indexed | 2024-09-23T13:18:31Z |
| format | Article |
| id | mit-1721.1/105537 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:18:31Z |
| publishDate | 2016 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/1055372022-10-01T14:25:43Z Chemical Genomics-Based Antifungal Drug Discovery: Targeting Glycosylphosphatidylinositol (GPI) Precursor Biosynthesis Mann, Paul A. Koseoglu, Sandra Si, Qian Kuzmin, Elena Flattery, Amy Harris, Guy Sher, Xinwei Murgolo, Nicholas Wang, Hao Devito, Kristine de Pedro, Nuria Genilloud, Olga Kahn, Jennifer Nielsen Jiang, Bo Costanzo, Michael Boone, Charlie Garlisi, Charles G. Roemer, Terry McLellan, Catherine Lindquist, Susan Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research McLellan, Catherine Lindquist, Susan Steadily increasing antifungal drug resistance and persistent high rates of fungal-associated mortality highlight the dire need for the development of novel antifungals. Characterization of inhibitors of one enzyme in the GPI anchor pathway, Gwt1, has generated interest in the exploration of targets in this pathway for further study. Utilizing a chemical genomics-based screening platform referred to as the Candida albicans fitness test (CaFT), we have identified novel inhibitors of Gwt1 and a second enzyme in the glycosylphosphatidylinositol (GPI) cell wall anchor pathway, Mcd4. We further validate these targets using the model fungal organism Saccharomyces cerevisiae and demonstrate the utility of using the facile toolbox that has been compiled in this species to further explore target specific biology. Using these compounds as probes, we demonstrate that inhibition of Mcd4 as well as Gwt1 blocks the growth of a broad spectrum of fungal pathogens and exposes key elicitors of pathogen recognition. Interestingly, a strong chemical synergy is also observed by combining Gwt1 and Mcd4 inhibitors, mirroring the demonstrated synthetic lethality of combining conditional mutants of GWT1 and MCD4. We further demonstrate that the Mcd4 inhibitor M720 is efficacious in a murine infection model of systemic candidiasis. Our results establish Mcd4 as a promising antifungal target and confirm the GPI cell wall anchor synthesis pathway as a promising antifungal target area by demonstrating that effects of inhibiting it are more general than previously recognized. Genome Canada (Firm) Genome Quebec 2016-12-02T19:27:27Z 2016-12-02T19:27:27Z 2014-12 2014-11 Article http://purl.org/eprint/type/JournalArticle 2373-8227 http://hdl.handle.net/1721.1/105537 Mann, Paul A. et al. “Chemical Genomics-Based Antifungal Drug Discovery: Targeting Glycosylphosphatidylinositol (GPI) Precursor Biosynthesis.” ACS Infectious Diseases 1.1 (2015): 59–72. © 2014 American Chemical Society https://orcid.org/0000-0003-1307-882X en_US http://dx.doi.org/10.1021/id5000212 ACS Infectious Diseases Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Chemical Society (ACS) ACS |
| spellingShingle | Mann, Paul A. Koseoglu, Sandra Si, Qian Kuzmin, Elena Flattery, Amy Harris, Guy Sher, Xinwei Murgolo, Nicholas Wang, Hao Devito, Kristine de Pedro, Nuria Genilloud, Olga Kahn, Jennifer Nielsen Jiang, Bo Costanzo, Michael Boone, Charlie Garlisi, Charles G. Roemer, Terry McLellan, Catherine Lindquist, Susan Chemical Genomics-Based Antifungal Drug Discovery: Targeting Glycosylphosphatidylinositol (GPI) Precursor Biosynthesis |
| title | Chemical Genomics-Based Antifungal Drug Discovery: Targeting Glycosylphosphatidylinositol (GPI) Precursor Biosynthesis |
| title_full | Chemical Genomics-Based Antifungal Drug Discovery: Targeting Glycosylphosphatidylinositol (GPI) Precursor Biosynthesis |
| title_fullStr | Chemical Genomics-Based Antifungal Drug Discovery: Targeting Glycosylphosphatidylinositol (GPI) Precursor Biosynthesis |
| title_full_unstemmed | Chemical Genomics-Based Antifungal Drug Discovery: Targeting Glycosylphosphatidylinositol (GPI) Precursor Biosynthesis |
| title_short | Chemical Genomics-Based Antifungal Drug Discovery: Targeting Glycosylphosphatidylinositol (GPI) Precursor Biosynthesis |
| title_sort | chemical genomics based antifungal drug discovery targeting glycosylphosphatidylinositol gpi precursor biosynthesis |
| url | http://hdl.handle.net/1721.1/105537 https://orcid.org/0000-0003-1307-882X |
| work_keys_str_mv | AT mannpaula chemicalgenomicsbasedantifungaldrugdiscoverytargetingglycosylphosphatidylinositolgpiprecursorbiosynthesis AT koseoglusandra chemicalgenomicsbasedantifungaldrugdiscoverytargetingglycosylphosphatidylinositolgpiprecursorbiosynthesis AT siqian chemicalgenomicsbasedantifungaldrugdiscoverytargetingglycosylphosphatidylinositolgpiprecursorbiosynthesis AT kuzminelena chemicalgenomicsbasedantifungaldrugdiscoverytargetingglycosylphosphatidylinositolgpiprecursorbiosynthesis AT flatteryamy chemicalgenomicsbasedantifungaldrugdiscoverytargetingglycosylphosphatidylinositolgpiprecursorbiosynthesis AT harrisguy chemicalgenomicsbasedantifungaldrugdiscoverytargetingglycosylphosphatidylinositolgpiprecursorbiosynthesis AT sherxinwei chemicalgenomicsbasedantifungaldrugdiscoverytargetingglycosylphosphatidylinositolgpiprecursorbiosynthesis AT murgolonicholas chemicalgenomicsbasedantifungaldrugdiscoverytargetingglycosylphosphatidylinositolgpiprecursorbiosynthesis AT wanghao chemicalgenomicsbasedantifungaldrugdiscoverytargetingglycosylphosphatidylinositolgpiprecursorbiosynthesis AT devitokristine chemicalgenomicsbasedantifungaldrugdiscoverytargetingglycosylphosphatidylinositolgpiprecursorbiosynthesis AT depedronuria chemicalgenomicsbasedantifungaldrugdiscoverytargetingglycosylphosphatidylinositolgpiprecursorbiosynthesis AT genilloudolga chemicalgenomicsbasedantifungaldrugdiscoverytargetingglycosylphosphatidylinositolgpiprecursorbiosynthesis AT kahnjennifernielsen chemicalgenomicsbasedantifungaldrugdiscoverytargetingglycosylphosphatidylinositolgpiprecursorbiosynthesis AT jiangbo chemicalgenomicsbasedantifungaldrugdiscoverytargetingglycosylphosphatidylinositolgpiprecursorbiosynthesis AT costanzomichael chemicalgenomicsbasedantifungaldrugdiscoverytargetingglycosylphosphatidylinositolgpiprecursorbiosynthesis AT boonecharlie chemicalgenomicsbasedantifungaldrugdiscoverytargetingglycosylphosphatidylinositolgpiprecursorbiosynthesis AT garlisicharlesg chemicalgenomicsbasedantifungaldrugdiscoverytargetingglycosylphosphatidylinositolgpiprecursorbiosynthesis AT roemerterry chemicalgenomicsbasedantifungaldrugdiscoverytargetingglycosylphosphatidylinositolgpiprecursorbiosynthesis AT mclellancatherine chemicalgenomicsbasedantifungaldrugdiscoverytargetingglycosylphosphatidylinositolgpiprecursorbiosynthesis AT lindquistsusan chemicalgenomicsbasedantifungaldrugdiscoverytargetingglycosylphosphatidylinositolgpiprecursorbiosynthesis |