Document Type : Original Articles
Authors
1
Eskisehir Osmangazi University, Vocational Health Services High School, Eskisehir, Turkey
2
Istanbul University Cerrahpasa Faculty of Medicine, Department of Medical Microbiology, Istanbul, 34098, Turkey
3
Department of Medical Microbiology, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey
4
Department of Medical Microbiology, University of Health Sciences, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
5
University of Health Sciences, Haydarpasa Numune Training and Research Hospital, Department of Medical Microbiology, Istanbul
6
Eskisehir Osmangazi University, Faculty of Medicine, Department of Medical Microbiology, Eskisehir, 26040, Turkey
10.22034/cmm.2025.345338.1601
Abstract
Background and Purpose: Due to the high morbidity and mortality caused by invasive mold infections, new and effective treatment strategies are needed. Heat shock proteins (Hsps) are found in all living organisms and they play a role in the homeostatic control of the cell and the stress response mediated by calcineurin. Their release increases especially in stress condition and they play a role in ensuring the stability of cellular proteins. Therefore, inhibition of Hsp90 or calcineurin may be an effective way in antifungal therapy. The aim of this study was to evaluate the in vitro activity of four different antifungal drugs (caspofungin, amphotericin B, itraconazole and voriconazole) in combination with fungal stress response regulators, Hsp90 inhibitors and calcineurin inhibitors, against clinical isolates of Aspergillus, Rhizopus and Fusarium.
Materials and Methods: In this study, the effectiveness of Hsp90 inhibitors geldanamycin (GELD), 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), radicicol (RDC), novobiosin (NOV) and calcineurin inhibitors cyclosporine (CICA), tacrolimus (TAC) and rapamycin (RAP) were combined with common antifungals itraconazole (ITRA), voriconazole (VOR), caspofungin (CAS) and amphotericin B (AMB) were investigated against 4 Aspergillus, 3 Rhizopus and 3 Fusarium isolates by using checkerboard method.
Results: The MIC/MEC values of ITRA, VOR, CAS and AMB were ≤0.25, ≤0.06-0.125, ≤0.03->4 and 1-4 µg/mL for Aspergillus spp.; 2-8, >4, >4 and 2 µg/mL for Rhizopus spp.; 8->16, 1-4, >4 and 2-4 µg/mL for Fusarium spp., respectively. Although tacrolimus was found to have generally low MIC values (≤0.03 µg/mL) for Aspergillus and Rhizopus isolates, novobiocin and 17-AAG did not exhibit antifungal activity (MICs>128 and ≥16 µg/mL, respectively) against almost all of the isolates. In combination testing against Aspergillus and Rhizopus spp., synergistic interactions were prevalent (≥75%) for the combinations of ITRA and all inhibitory substances except for TAC. The effects of CAS and TAC in combination tests were weak. Also, synergistic interactions were not frequent in all combinations against Fusarium spp. However, antagonistic interaction was observed only in one ITRA and RAP combination in all of this study.
Conclusion: Although Hsp90 and calcineurin inhibitors alone did not have significant antifungal activity, they did not show a significant antagonistic effect in combination, and even increased the efficacy of antifungals at some concentrations.
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