Adh1-Programmed SNF1 Phosphogradients Decrypt Morphogenesis in Candida albicans: Chemical Interrogation Unveils...

Area of Science:

• Microbiology
• Biochemistry
• Drug Discovery

Background:

• Candida albicans alcohol dehydrogenase I (Adh1) is traditionally known for alcohol metabolism.
• Previous research suggests Adh1 has a non-canonical role in fungal development.

Purpose of the Study:

• To redefine the role of Adh1 in Candida albicans hyphal morphogenesis.
• To elucidate the molecular mechanisms underlying Adh1's regulation of hyphal growth.
• To identify novel inhibitors targeting Adh1 for antifungal therapy.

Main Methods:

• Phenotypic analysis of Adh1 knockout strains.
• High-throughput screening using a reverse screening strategy.
• Biochemical and structural analyses of compound-protein interactions.
• Affinity purification-mass spectrometry to identify interacting partners.

Main Results:

• Adh1 knockout strains display hyperfilamentation, indicating Adh1's role in suppressing hyphal development.
• 2-hydroxyanthraquinone (HAQ) was identified as a potent inhibitor of Adh1, blocking hyphal growth and biofilm formation.
• HAQ directly binds to Adh1 at the F224/A254/Q257 interface.
• Adh1 modulates the SNF1 signaling pathway by promoting dephosphorylation via Bmh1/Ssb1, and HAQ disrupts this interaction.

Conclusions:

• Adh1 acts as an endogenous suppressor of the SNF1 pathway, inhibiting hyphal development in Candida albicans.
• Adh1 represents a novel drug target for antifungal development.
• HAQ is a validated lead compound for developing new therapies against Candida albicans infections.