ArticleACS infectious diseases2015
Chemical Genomics-Based Antifungal Drug Discovery: Targeting Glycosylphosphatidylinositol (GPI) Precursor Biosynthesis.
Article in ACS infectious diseases, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 82 citations in OpenAlex.
- Fosmanogepix: A comprehensive review of its origin, mechanism, antifungal efficacy, and resistance (Review).Biomedical reports · 2026Review
- Molecular insights into Candida auris glycosylphosphatidylinositol transamidase.Protein & cell · 2026Article
- Rho2-dependent cell wall remodeling boosts the fungistatic activity of manogepix againstCell surface (Amsterdam, Netherlands) · 2026Article
- Identification of GPI-Anchored Wall Transfer Protein 1 Modulators for Fungal Infections Through Generative AI and Physics-Based Approaches.International journal of molecular sciences · 2026Article
- Review
- Molecular Insights into Fungal Glycosylphosphatidylinositol Transamidase Complex.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Structural Insights into the Glycosylphosphatidylinositol Mannosyltransferase I Complex fromJournal of fungi (Basel, Switzerland) · 2025Article
- Next-generation antifungal drugs: Mechanisms, efficacy, and clinical prospects.Acta pharmaceutica Sinica. B · 2025Review
- Interdisciplinary approaches for the discovery of novel antifungals.Trends in molecular medicine · 2024Review
- To each its own: Mechanisms of cross-talk between GPI biosynthesis and cAMP-PKA signaling in Candida albicans versus Saccharomyces cerevisiae.The Journal of biological chemistry · 2024Review
- Review
- Protein lipidation in health and disease: molecular basis, physiological function and pathological implication.Signal transduction and targeted therapy · 2024Review
- Molecular basis of the inositol deacylase PGAP1 involved in quality control of GPI-AP biogenesis.Nature communications · 2024Article
- Structure and Function of the Glycosylphosphatidylinositol Transamidase, a Transmembrane Complex Catalyzing GPI Anchoring of Proteins.Sub-cellular biochemistry · 2024Review
- Discovery of a new chemical scaffold for the treatment of superbugEmerging microbes & infections · 2023Article
- The Mechanism of Transcription Factor Swi6 in Regulating Growth and Pathogenicity ofMicroorganisms · 2023Article
- Fungal Drug Response and Antimicrobial Resistance.Journal of fungi (Basel, Switzerland) · 2023Review
- Beyond Ergosterol: Strategies for Combatting Antifungal Resistance inTetrahedron · 2023Article
- Chemical-Genetic Approaches for Exploring Mode of Action of Antifungal Compounds in the Fungal Pathogen Candida albicans.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Calcineurin Inhibitors Synergize with Manogepix to Kill Diverse Human Fungal Pathogens.Journal of fungi (Basel, Switzerland) · 2022Article
Corrections and comments
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Authors and funding
20 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.