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Volume 15
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10.3390/pathogens15020185
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Article

HTD1265 Disrupts GimC-Dependent Cellular Processes in Saccharomyces cerevisiae

by
Kaori Itto-Nakama
1,
Naoya Hosoyamada
1,
Shinsuke Ohnuki
1,
Fumiyuki Shirai
2,
Minagi Mukaiyama
3,
Hiroyuki Hirano
2,
Hiroyuki Osada
4,
Charles Boone
2,5,
Takeo Usui
3,
Yoko Yashiroda
2 and
Yoshikazu Ohya
1,6,7,*
1
Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwano-ha, Kashiwa 277-8562, Chiba, Japan
2
RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako 351-0198, Saitama, Japan
3
Institute of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8572, Ibaraki, Japan
4
Institute of Microbial Chemistry (BIKAKEN), 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
5
Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada
6
Collaborative Research Institute for Innovative Microbiology (CRIIM), The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
7
Department of Science and Technology Innovation, Nagaoka University of Technology, 1603-1 Kamitoyooka-cho, Nagaoka 940-2137, Niigata, Japan
*
Author to whom correspondence should be addressed.
Pathogens 2026, 15(2), 185; https://doi.org/10.3390/pathogens15020185
Submission received: 16 January 2026 / Revised: 2 February 2026 / Accepted: 3 February 2026 / Published: 7 February 2026
(This article belongs to the Special Issue Emerging and Rare Fungal Pathogens in a Changing World)
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Abstract

HTD1265 is a newly identified antifungal compound that displays potent activity against Candida krusei, a clinically challenging non-albicans species. To elucidate its mechanism of action, we applied an integrative phenotypic approach combining high-resolution morphological profiling, pathway inference, and genetic validation in Saccharomyces cerevisiae. Morphological signature extraction revealed a characteristic defect in nuclear positioning upon HTD1265 treatment. Integration of nuclear positioning traits with global morphological similarity highlighted 36 genes enriched for the Gene Ontology term “tubulin complex assembly.” Consistent with this prediction, HTD1265 impaired mitotic spindle elongation without directly inhibiting tubulin polymerization. HTD1265 further induced hallmarks of GimC (prefoldin) deficiency, including aberrant chitin accumulation, actin disorganization, and nuclear mispositioning, and caused hypersensitivity in GimC subunit mutants. These converging observations suggest that HTD1265 exerts antifungal activity by disrupting GimC-dependent cellular processes rather than by directly targeting tubulin. Our findings highlight GimC-dependent cytoskeletal and cell wall regulatory processes as a critical vulnerability for fungal growth and position HTD1265 as a functional tool for dissecting this pathway.
Keywords: Saccharomyces cerevisiae; antifungal agents; GimC (prefoldin); Candida krusei Saccharomyces cerevisiae; antifungal agents; GimC (prefoldin); Candida krusei

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MDPI and ACS Style

Itto-Nakama, K.; Hosoyamada, N.; Ohnuki, S.; Shirai, F.; Mukaiyama, M.; Hirano, H.; Osada, H.; Boone, C.; Usui, T.; Yashiroda, Y.; et al. HTD1265 Disrupts GimC-Dependent Cellular Processes in Saccharomyces cerevisiae. Pathogens 2026, 15, 185. https://doi.org/10.3390/pathogens15020185

AMA Style

Itto-Nakama K, Hosoyamada N, Ohnuki S, Shirai F, Mukaiyama M, Hirano H, Osada H, Boone C, Usui T, Yashiroda Y, et al. HTD1265 Disrupts GimC-Dependent Cellular Processes in Saccharomyces cerevisiae. Pathogens. 2026; 15(2):185. https://doi.org/10.3390/pathogens15020185

Chicago/Turabian Style

Itto-Nakama, Kaori, Naoya Hosoyamada, Shinsuke Ohnuki, Fumiyuki Shirai, Minagi Mukaiyama, Hiroyuki Hirano, Hiroyuki Osada, Charles Boone, Takeo Usui, Yoko Yashiroda, and et al. 2026. "HTD1265 Disrupts GimC-Dependent Cellular Processes in Saccharomyces cerevisiae" Pathogens 15, no. 2: 185. https://doi.org/10.3390/pathogens15020185

APA Style

Itto-Nakama, K., Hosoyamada, N., Ohnuki, S., Shirai, F., Mukaiyama, M., Hirano, H., Osada, H., Boone, C., Usui, T., Yashiroda, Y., & Ohya, Y. (2026). HTD1265 Disrupts GimC-Dependent Cellular Processes in Saccharomyces cerevisiae. Pathogens, 15(2), 185. https://doi.org/10.3390/pathogens15020185

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