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Gwt1

  • <em>In Vitro</em> Activity of Manogepix against Multidrug-Resistant and Panresistant <span class="named-content genus-species" id="named-content-1">Candida auris</span> from the New York Outbreak
    Susceptibility
    In Vitro Activity of Manogepix against Multidrug-Resistant and Panresistant Candida auris from the New York Outbreak

    An ongoing Candida auris outbreak in the New York metropolitan area is the largest recorded to date in North America. Laboratory surveillance revealed NY C. auris isolates are resistant to fluconazole, with variable resistance to other currently used broad-spectrum antifungal drugs, and that several...

    YanChun Zhu, Shannon Kilburn, Mili Kapoor, Sudha Chaturvedi, Karen Joy Shaw, Vishnu Chaturvedi
  • Antifungal Activity of Gepinacin Scaffold Glycosylphosphatidylinositol Anchor Biosynthesis Inhibitors with Improved Metabolic Stability
    Experimental Therapeutics
    Antifungal Activity of Gepinacin Scaffold Glycosylphosphatidylinositol Anchor Biosynthesis Inhibitors with Improved Metabolic Stability

    The glycosylphosphatidylinositol anchor biosynthesis inhibitor gepinacin demonstrates broad-spectrum antifungal activity and negligible mammalian toxicity in culture but is metabolically labile. The stability and bioactivity of 39 analogs were tested in vitro to identify LCUT-8, a stabilized lead with increased potency and promising single-dose pharmacokinetics. Unfortunately, no antifungal activity was seen at the maximum...

    Sean D. Liston, Luke Whitesell, Catherine A. McLellan, Ralph Mazitschek, Vidmantas Petraitis, Ruta Petraitiene, Povilas Kavaliauskas, Thomas J. Walsh, Leah E. Cowen
  • Open Access
    Fosmanogepix (APX001) Is Effective in the Treatment of Pulmonary Murine Mucormycosis Due to <span class="named-content genus-species" id="named-content-1">Rhizopus arrhizus</span>
    Experimental Therapeutics
    Fosmanogepix (APX001) Is Effective in the Treatment of Pulmonary Murine Mucormycosis Due to Rhizopus arrhizus

    Mucormycosis is a life-threatening infection with high mortality that occurs predominantly in immunocompromised patients. Manogepix (MGX) is a novel antifungal that targets Gwt1, a protein involved in an early step in the conserved glycosylphosphotidyl inositol (GPI) posttranslational modification pathway of surface proteins in eukaryotic cells. Inhibition of fungal inositol acylation by MGX results in pleiotropic effects, including...

    Teclegiorgis Gebremariam, Sondus Alkhazraji, Abdullah Alqarihi, Nathan P. Wiederhold, Karen Joy Shaw, Thomas F. Patterson, Scott G. Filler, Ashraf S. Ibrahim
  • Open Access
    Enhanced Efflux Pump Expression in <em>Candida</em> Mutants Results in Decreased Manogepix Susceptibility
    Mechanisms of Resistance
    Enhanced Efflux Pump Expression in Candida Mutants Results in Decreased Manogepix Susceptibility

    Manogepix is a broad-spectrum antifungal agent that inhibits glycosylphosphatidylinositol (GPI) anchor biosynthesis. Using whole-genome sequencing, we characterized two efflux-mediated mechanisms in the fungal pathogens Candida albicans and Candida parapsilosis that resulted in decreased manogepix...

    Sean D. Liston, Luke Whitesell, Mili Kapoor, Karen Joy Shaw, Leah E. Cowen
  • Open Access
    Fosmanogepix (APX001) Is Effective in the Treatment of Immunocompromised Mice Infected with Invasive Pulmonary Scedosporiosis or Disseminated Fusariosis
    Editor's Pick Experimental Therapeutics
    Fosmanogepix (APX001) Is Effective in the Treatment of Immunocompromised Mice Infected with Invasive Pulmonary Scedosporiosis or Disseminated Fusariosis

    There are limited treatment options for immunosuppressed patients with lethal invasive fungal infections due to Fusarium and Scedosporium. Manogepix (MGX; APX001A) is a novel antifungal that targets the conserved Gwt1 enzyme required for localization of glycosylphosphatidylinositol-anchored mannoproteins in fungi. We evaluated the in vitro activity of MGX and the efficacy of the prodrug fosmanogepix (APX001)...

    Sondus Alkhazraji, Teclegiorgis Gebremariam, Abdullah Alqarihi, Yiyou Gu, Zeinab Mamouei, Shakti Singh, Nathan P. Wiederhold, Karen J. Shaw, Ashraf S. Ibrahim
  • Open Access
    Galactomannan Is a Biomarker of Fosmanogepix (APX001) Efficacy in Treating Experimental Invasive Pulmonary Aspergillosis
    Experimental Therapeutics
    Galactomannan Is a Biomarker of Fosmanogepix (APX001) Efficacy in Treating Experimental Invasive Pulmonary Aspergillosis

    Galactomannan (GM) detection in biological samples has been shown to predict therapeutic response by azoles and polyenes. In a murine invasive pulmonary aspergillosis model, fosmanogepix or posaconazole treatment resulted in an ∼6- to 7-log reduction in conidial equivalents (CE)/g lung tissue after 96 h versus placebo.

    Teclegiorgis Gebremariam, Sondus Alkhazraji, Yiyou Gu, Shakti Singh, Abdullah Alqarihi, Karen Joy Shaw, Ashraf S. Ibrahim
  • Open Access
    Evaluation of Resistance Development to the Gwt1 Inhibitor Manogepix (APX001A) in <em>Candida</em> Species
    Mechanisms of Resistance
    Evaluation of Resistance Development to the Gwt1 Inhibitor Manogepix (APX001A) in Candida Species

    Manogepix (MGX) targets the conserved fungal Gwt1 enzyme required for acylation of inositol early in the glycosylphosphatidylinositol biosynthesis pathway. The prodrug fosmanogepix is currently in clinical development for the treatment of invasive fungal infections.

    Mili Kapoor, Molly Moloney, Quinlyn A. Soltow, Chris M. Pillar, Karen Joy Shaw
  • Open Access
    Efficacy of Delayed Therapy with Fosmanogepix (APX001) in a Murine Model of <span class="named-content genus-species" id="named-content-1">Candida auris</span> Invasive Candidiasis
    Experimental Therapeutics
    Efficacy of Delayed Therapy with Fosmanogepix (APX001) in a Murine Model of Candida auris Invasive Candidiasis

    The emerging pathogenic yeast Candida auris is associated with antifungal resistance and high mortality. The novel antifungal agent manogepix (APX001A) inhibits glycosylphosphatidylinositol-anchored protein maturation and has demonstrated activity against numerous pathogenic fungi, including C. auris...

    Nathan P. Wiederhold, Laura K. Najvar, Karen J. Shaw, Rosie Jaramillo, Hoja Patterson, Marcos Olivo, Gabriel Catano, Thomas F. Patterson
  • <em>In Vitro</em> Activity of APX001A (Manogepix) and Comparator Agents against 1,706 Fungal Isolates Collected during an International Surveillance Program in 2017
    Susceptibility
    In Vitro Activity of APX001A (Manogepix) and Comparator Agents against 1,706 Fungal Isolates Collected during an International Surveillance Program in 2017

    Current antifungal agents cover a majority of opportunistic fungal pathogens; however, breakthrough invasive fungal infections continue to occur and increasingly involve relatively uncommon yeasts and molds, which often exhibit decreased susceptibility. APX001A (manogepix) is a first-in-class small-molecule inhibitor of the conserved fungal Gwt1 protein. This enzyme is required for acylation of inositol during...

    M. A. Pfaller, M. D. Huband, R. K. Flamm, P. A. Bien, M. Castanheira
  • Open Access
    APX001 and Other Gwt1 Inhibitor Prodrugs Are Effective in Experimental <em>Coccidioides immitis</em> Pneumonia
    Experimental Therapeutics
    APX001 and Other Gwt1 Inhibitor Prodrugs Are Effective in Experimental Coccidioides immitis Pneumonia

    Coccidioidomycosis is a systemic fungal infection caused by the inhalation of the arthroconidia of either of two closely related dimorphic fungi, Coccidioides immitis and C. posadasii, that are endemic in the southwestern United States and other areas in the Western Hemisphere. Chronic cavitary...

    Suganya Viriyakosol, Mili Kapoor, Sharon Okamoto, Jonathan Covel, Quinlyn A. Soltow, Michael Trzoss, Karen Joy Shaw, Joshua Fierer

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