title: 9-O-butyl-13-(4-isopropylbenzyl)berberine, KR-72, is a potent antifungal agent that inhibits the growth of Cryptococcus neoformans by regulating gene expression.
abstract: In this study we explored the mode of action of KR-72, a 9-O-butyl-13-(4-isopropylbenzyl)berberine derivative previously shown to exhibit potent antifungal activity against a variety of human fungal pathogens. The DNA microarray data revealed that KR-72 treatment significantly changed the transcription profiles of C. neoformans, affecting the expression of more than 2,000 genes. Genes involved in translation and transcription were mostly upregulated, whereas those involved in the cytoskeleton, intracellular trafficking, and lipid metabolism were downregulated. KR-72 also exhibited a strong synergistic effect with the antifungal agent FK506. KR-72 treatment regulated the expression of several essential genes, including ECM16, NOP14, HSP10 and MGE1, which are required for C. neoformans growth. The KR-72-mediated induction of MGE1 also likely reduced the viability of C. neoformans by impairing cell cycle or the DNA repair system. In conclusion, KR-72 showed antifungal activity by modulating diverse biological processes through a mode of action distinct from those of clinically available antifungal drugs such as polyene and azole drugs.
authors.affiliation: Department of Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors.forename: Soohyun
authors.initials: S
authors.lastname: Bang
authors.affiliation: Department of Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors.forename: Hyojeong
authors.initials: H
authors.lastname: Kwon
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea.
authors.forename: Hyun Sook
authors.initials: HS
authors.lastname: Hwang
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea.
authors.forename: Ki Duk
authors.initials: KD
authors.lastname: Park
authors.affiliation: Industrial Bio-materials Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Sung Uk
authors.initials: SU
authors.lastname: Kim
authors.affiliation: Department of Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors.forename: Yong-Sun
authors.initials: YS
authors.lastname: Bahn
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001600:Berberine Alkaloids / Q000494:pharmacology*; D003455:Cryptococcus neoformans / Q000187:drug effects* / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects*; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects*; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: D000935:Antifungal Agents; D001600:Berberine Alkaloids