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bioRxiv · 10.1101/2024.05.25.595862

Antifungal potency of terbinafine as a therapeutic agent against Exophiala dermatitidis in vitro

Nakamura, T.·Yoshinouchi, T.·Okumura, M.·Yokoyama, T.·Mori, D.·Nakata, H.·Yasunaga, J.-i.·Tanaka, Y.
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Abstract

SynopsisO_ST_ABSBackgroundC_ST_ABSExophiala dermatitidis (E. dermatitidis), which causes skin infections or respiratory diseases, is occasionally fatal in immunocompromised patients. ObjectivesHere, we report the unique antifungal potency of terbinafine (TRB), which targets squalene epoxidase, against E. dermatitidis (SQLEED) using various in vitro approaches. MethodsBased on the human SQLE crystal structure, we created a structure model of SQLEED using SWISS-MODEL and determined the best-fitting model of TRB to the SQLEED. The versatile antifungal activities, including fungicidal activity, biofilm inhibition, biofilm eradication activity, and the combination effect of TRB, posaconazole (PSC), and amphotericin B (AmB) with great antifungal potency against E. dermatitidis were evaluated using crystal violet and cell viability assay. ResultsClinically isolated E. dermatitidis increased most vigorously at 30{degrees}C but decreased at 40{degrees}C. E. dermatitidis hyphae elongated and attached to a cell scaffold, forming a membrane-like biofilm that was distinct from the cell-free biofilm. In the binding model, TRB formed an H-bond with Y102 and was surrounded by key amino acid residues of SQLEED corresponding to TRB-resistant mutations in Trichophyton rubrum, showing an appropriate interaction. Among TRB, PSC, and AmB with potent antifungal activities, TRB and PSC showed more potent antibiofilm activities than AmB. In addition, TRB and PSC exhibited residual potency without incubation against E. dermatitidis, decreasing the growth at lower concentrations than AmB. In contrast, AmB exhibited strong time-dependent killing and eradication activities. The combination of TRB and PSC was more effective than that of TRB and AmB or PSC and AmB in vitro. ConclusionsAlthough the tissue migration of TRB must be considered, these data suggest that TRB and PSC may be useful agents and a potent combination in severely immunocompromised patients with refractory and systemic E. dermatitidis infection.

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Nakamura, T., Yoshinouchi, T., Okumura, M., Yokoyama, T., Mori, D., Nakata, H., Yasunaga, J.-i., Tanaka, Y.. 2024-05-25. Antifungal potency of terbinafine as a therapeutic agent against Exophiala dermatitidis in vitro. https://doi.org/10.1101/2024.05.25.595862

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