Evaluation of the efficacy of heat shock protein inhibitors and antifungal drug combinations against Candida spp

• Published in: Atti della Accademia nazionale dei Lincei. Rendiconti Lincei. Scienze fisiche e naturali Vol. 34; no. 1; pp. 179 - 188
• Main Authors: Kiraz, Nuri, Şen Kaya, Sümeyye, Öz, Yasemin, Dağ, İlknur
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-03-2023; Springer Nature B.V
• Subjects: Amphotericin B; Antifungal activity; Antifungal agents; Biomedicine; Candida; Caspofungin; Drug delivery; Drug interaction; Drug resistance; Drugs; Earth and Environmental Science; Earth Sciences; Effectiveness; Environment; Fluconazole; Fungal infections; Fungi; Fungicides; Geldanamycin; Health risks; Heat shock proteins; History of Science; Hsp90 protein; Immunosuppressive agents; Infections; Inhibitors; Itraconazole; Life Sciences; Novobiocin; Physics; Research Paper; Toxicity; Voriconazole; Hsp90 inhibitors; Antifungal susceptibility; Combination therapy
• ISSN: 2037-4631; 1720-0776
• DOI: 10.1007/s12210-022-01118-0

Candida
species are one of the predominant causes of fungal infections and show drug-resistant infections in immune-compromised individuals. Simultaneous targeting of existing antifungal drugs with heat shock protein 90 (Hsp90) inhibitors may be an approach that increases the efficacy of antifungal drugs. Also, since most of the patients at risk for invasive fungal infections use these anticancer or immunosuppressive drugs, synergistic interaction in combination treatment can reduce the dose of antifungal drugs and create an alternative for the toxicity problem. In this study, in vitro efficacy of commonly used antifungals (amphotericin B, caspofungin, itraconazole, voriconazole, and fluconazole) in combination with four heat shock protein inhibitors geldanamycin, 17-allylamino-17-demethoxygeldanamycin, radicicol, and novobiocin against 30 clinical
Candida
isolates (
C. albicans
n
 = 13,
C. krusei
n
 = 7, and
C. glabrata
n
 = 10) were evaluated by time kill and checkerboard methods. The significant synergistic interaction determined especially in the combinations of geldanamycin with antifungal drugs suggests that substances with inhibitory effects on Hsp90 increase the effectiveness of antifungals or reduce the antifungal resistance. Although Hsp90 inhibitors alone did not have any significant antifungal activity, they did not show adverse interactions in combination with antifungals, and at some concentrations, they increased the effectiveness of the antifungals. These in vitro results have been found promising for the development of new therapeutic approaches in the treatment of invasive fungal infections. However, detailed studies are needed.