Blocking assembly of glycosylphosphatidylinositol (GPI) anchors to inhibit growth and increase immunogenicity of human fungal pathogens
Fungal pathogens cause life-threatening invasive infections in humans. Despite all available treatments, mortality rates remain unacceptably high, on par with deaths caused by infectious diseases such as tuberculosis and malaria. Alarmingly, the emergence of drug-resistant fungi is reducing already limited treatment options. To address needs for new antifungal medications, Amplyx Pharmaceuticals has developed fosmanogepix, a drug which attacks fungi by blocking their ability to build their cell wall, a structure needed to survive and invade humans. To better understand how this drug works and the best way to use it, the objectives of my work are to (1) determine precisely how this drug alters the fungal cell wall, and (2) determine the structure of the drug’s direct target, the fungal protein Gwt1. Understanding how fosmanogepix binds to Gwt1 at the molecular level will help with development of derivatives that will be more effective and cause fewer side-effects in patients.