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Evaluation of the combined efficacy of inhibitors of heat shock protein 90 and calcineurin with commonly used antifungals against Aspergillus, Rhizopus, and Fusarium isolates

Summary

Scientists tested combinations of common antifungal medications with special inhibitor drugs that target fungal stress-response systems. When combined, these drugs worked better together against dangerous mold infections like Aspergillus and Rhizopus, especially those that are resistant to standard treatments. The combinations rarely caused harmful interactions and often enhanced the antifungal effects, suggesting this approach could improve treatment of serious mold infections.

Background

Invasive mold infections caused by Aspergillus, Rhizopus, and Fusarium species have high morbidity and mortality rates with limited treatment options due to emerging antifungal resistance. Heat shock protein 90 (Hsp90) and calcineurin are important regulators of fungal stress response and adaptation. Targeting these pathways in combination with antifungals represents a promising therapeutic strategy.

Objective

This study evaluated the in vitro activity of four antifungal agents (caspofungin, amphotericin B, itraconazole, and voriconazole) in combination with Hsp90 inhibitors and calcineurin inhibitors against clinical isolates of Aspergillus, Rhizopus, and Fusarium species.

Results

Among inhibitors, tacrolimus showed the most potent activity against Aspergillus and Rhizopus isolates, while novobiocin and 17-AAG showed minimal activity. In combination testing of 280 combinations, synergistic interactions were observed in 33% of cases, with ITRA combinations showing the most synergy. Only one antagonistic interaction was detected (RAP+ITRA). Synergistic interactions were less frequent against Fusarium isolates.

Conclusion

Hsp90 and calcineurin inhibitors showed minimal antifungal activity when used alone but enhanced antifungal efficacy in many combinations without significant antagonistic effects. These findings suggest that combining Hsp90/calcineurin inhibitors with conventional antifungals may be a promising strategy for managing invasive mold infections, particularly for azole-resistant strains.
  • Published in:Current Medical Mycology,
  • Study Type:In vitro experimental study,
  • Source: PMID: 41122121, DOI: 10.22034/cmm.2025.345248.1601
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