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Synergistic effects of Cyp51 isozyme-specific azole antifungal agents on fungi with multiple cyp51 isozyme genes

Summary

This study found that different azole antifungal drugs work better against different versions of an enzyme (Cyp51) that fungi need to survive. By combining two azole drugs that each target different enzyme versions, researchers achieved stronger antifungal effects than either drug alone. This discovery suggests a new strategy for treating stubborn fungal infections by carefully selecting drug combinations based on which enzyme versions the fungus possesses.

Background

Pathogenic fungi present therapeutic challenges due to limited drug targets related to their eukaryotic nature. Azole antifungals target Cyp51 enzyme in ergosterol biosynthesis, but some filamentous fungi possess multiple cyp51 genes with potentially distinct functions and drug sensitivities.

Objective

To investigate whether different Cyp51 isozymes exhibit distinct susceptibilities to azole antifungals and whether combining isozyme-selective agents produces synergistic antifungal effects in fungi with multiple cyp51 genes.

Results

Cyp51B was essential for basal mycelial growth while Cyp51A functioned as an inducible isozyme promoting azole tolerance. Different azoles demonstrated selective activities: fluconazole, sulconazole, and imazalil showed increased activity against Δcyp51A, while prochloraz showed increased activity against Δcyp51B. Combinations of these isozyme-selective agents produced synergistic effects (FIC ≤0.5) against wild-type strains and were also effective against Aspergillus welwitschiae.

Conclusion

Cyp51 isozyme selectivity represents an exploitable mechanism for antifungal synergy. Combining azole antifungals with different Cyp51 isozyme selectivities offers a promising therapeutic approach for treating fungal infections caused by organisms with multiple cyp51 genes, potentially opening new avenues for precision combination therapy development.
  • Published in:Antimicrobial Agents and Chemotherapy,
  • Study Type:In vitro experimental study,
  • Source: PMID: 41004213, DOI: 10.1128/aac.00598-25
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