Re-discovery of MS-347a as a fungicide candidate through a new drug discovery platform with a multidrug-sensitive Saccharomyces cerevisiae screening system and the introduction of a global secondary metabolism regulator, laeA gene

Sota Honma; Aoi Kimishima; Atsushi Kimishima; Masako Honsho; Hiroki Kojima; Toshiyuki Tokiwa; Atsuka Nishitomi; Satoshi Kato; Naozumi Kondo; Yasuko Araki; Tadashi Takahashi; Takumi Chinen; Takeo Usui; Shin-Ichi Fuji; Kotaro Ito; Yukihiro Asami

doi:10.1093/bbb/zbae050

Re-discovery of MS-347a as a fungicide candidate through a new drug discovery platform with a multidrug-sensitive Saccharomyces cerevisiae screening system and the introduction of a global secondary metabolism regulator, laeA gene

Biosci Biotechnol Biochem. 2024 Apr 25:zbae050. doi: 10.1093/bbb/zbae050. Online ahead of print.

Authors

Sota Honma^{1

2}, Aoi Kimishima^{1

2}, Atsushi Kimishima³, Masako Honsho^{1

2}, Hiroki Kojima^{1

2}, Toshiyuki Tokiwa^{1

2}, Atsuka Nishitomi¹, Satoshi Kato¹, Naozumi Kondo¹, Yasuko Araki⁴, Tadashi Takahashi⁴, Takumi Chinen⁵, Takeo Usui⁶, Shin-Ichi Fuji⁷, Kotaro Ito⁴, Yukihiro Asami^{1

2}

Affiliations

¹ Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
² Ōmura Satoshi Memorial Institute, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
³ Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
⁴ Research and Development Division, Kikkoman Corporation, 338 Noda, Noda-shii, Chiba, 278-0037, Japan.
⁵ Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences. The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
⁶ Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8572, Japan.
⁷ Faculty of Bioresource Sciences, Akita Prefectural University, 241-438 Kaidobata-Nishi, Nakano, Shimoshinjo, Akita, 010-0195, Japan.

PMID: 38664007
DOI: 10.1093/bbb/zbae050

Abstract

We found that the culture broth of fungi showed anti-fungal activity against multidrug-sensitive budding yeast. However, we could not identify the anti-fungal compound due to the small quantity. Therefore, we attempted to increase the productivity of the target compound by the introduction of a global secondary metabolism regulator, laeA to the strain, which led to the successful isolation of ten-folds greater amount of MS-347a (1) than Aspergillus sp. FKI-5362. Compound 1 was not effective against Candida albicans and the detailed anti-fungal activity of 1 remains unverified. After our anti-fungal activity screening, 1 was found to inhibit the growth of broad plant pathogenic fungal species belonging to the Ascomycota. It is noteworthy that 1 showed little insecticidal activity against silkworms, suggesting its selective biological activity against plant pathogenic fungi. Our study implies that the combination strategy of multidrug-sensitive yeast and the introduction of laeA is useful for new anti-fungal drug discovery.

Keywords: Aspergillus sp; Fungicide candidates; LaeA; Multidrug-sensitive budding yeast; Natural products.