17th JPIAMR transnational call for research projects - AMR Interventions 2024 (IMPACT)

General Information

• Project title: Discovery of first-in-class and new mechanism of action antifungal compounds targeting the fungal shikimate pathway
• Type: Project looking for partner
• Organisation: University of Toronto
• Country: Canada (CA)
• Career stage: Other.

Research area

• Scientific area(s) of the call:
  1. Topic 1: Design novel or improved interventions to prevent, mitigate and /or treat fungal infections, which are resistant to treatments and/or are at risk of developing resistance
• Subtopics:

• One Health Setting:

  Human Health

• Keywords:

  antifungal Candida structure-based drug design screenin chemistry

• Brief description of your expertise / expertise you are looking for:

  We are interested in antifungal drug discovery. We are structural biologists and biochemistry with deep expertise in characterization of antimicrobial drug targets and antimicrobial resistance-conferring proteins. We are looking for partners with expertise in synthetic and medicinal chemistry, assay design for high-throughput screening, and antimicrobial (antifungal) drug discovery and development.

• Brief description of your project / the project you would like to join:

  Fungal pathogens exact an enormous toll on human health and contribute to 1.5 million deaths worldwide per year. Candida albicans is a common commensal organism in the human body but it also causes life-threatening infections, and C. auris is a serious emerging pathogen that possesses intrinsic multi-drug resistance. These two species cause approximately 400,000 bloodstream infections per year worldwide. Currently, there are only 4 major classes of antifungals, each of which is increasingly threatened by resistance, especially in C. auris. The limited number of effective antifungals available and the rise of drug resistance contribute to poor clinical outcomes, thus, new antifungal drug targets and antifungal chemical matter are urgently needed. We have established that the shikimate pathway in Candida species represents a new antifungal drug target - see https://pubmed.ncbi.nlm.nih.gov/35512834. We have established that the activity of 4 of the 5 domains of the Aro1 enzyme are essential for Candida albicans viability, have put into place a variety of enzymatic, 3D structural and genetic tools for small molecule inhibitor drug discovery targeted to this enzyme, and have identified multiple hit compounds that inhibit the activity of Aro1. These data present a valuable opportunity for discovery of first-in-class antifungals with a new mechanism of action. The proposed goals of our project for JPIAMR are: 1) Advance hit compounds to lead status; 2) Discover new small molecule scaffolds with whole cell anti-fungal, on-Aro1 on-target activity; 3) Determine the spectrum of antifungal susceptibility and resistance mechanisms across pathogenic fungi species.

Peter Stogios

• Organisation: University of Toronto
• Position: Senior Research Associate
• E-mail: p.stogios@utoronto.ca