Acetohydroxyacid synthase inhibitors as chemotherapeutic agents for pathogenic invasive fungal infections — ASN Events
  1. Schedule
  2. Session Five - Poster Session A including Refreshments
  3. Acetohydroxyacid synthase inhibitors as chemotherapeutic agents for pathogenic invasive fungal infections

Acetohydroxyacid synthase inhibitors as chemotherapeutic agents for pathogenic invasive fungal infections (#112)

Mario Garcia 1 , Nason Pue 1 , Thierry Lonhienne 1 , Luke Guddat 1
  1. The University of Queensland, Brisbane, QLD, Australia

The sulfonylurea herbicides exert their activity by inhibiting plant acetohydroxyacid synthase (AHAS), the first enzyme in the branched-chain amino acid biosynthesis pathway. It has previously been shown that when the gene for AHAS is deleted in C. neoformans this pathogen is avirulent, and the equivalent mutation in C. albicans, leads to attenuation of virulence. Here, we have shown that members of the sulfonylurea family and several compounds found by fragment based screening are inhibitors of fungal AHASs. The most potent of these compounds, chlorimuron ethyl, has a Ki value of 7 nM for C. albicans AHAS and an MIC50 of 2 uM for this fungus in cell-based assays. The compounds tested displayed a strong correlation between inhibitory activity towards AHAS and fungicidal activity demonstrating that these compounds represent new leads in the development of chemotherapeutic agents to treat fungal pathogenic infections.