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

Soohyun Bang; Hyojeong Kwon; Hyun Sook Hwang; Ki Duk Park; Sung Uk Kim; Yong-Sun Bahn

doi:10.1371/journal.pone.0109863

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

PLoS One. 2014 Oct 10;9(10):e109863. doi: 10.1371/journal.pone.0109863. eCollection 2014.

Authors

Soohyun Bang¹, Hyojeong Kwon¹, Hyun Sook Hwang², Ki Duk Park², Sung Uk Kim³, Yong-Sun Bahn¹

Affiliations

¹ Department of Biotechnology, Yonsei University, Seoul, Republic of Korea.
² Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea.
³ Industrial Bio-materials Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antifungal Agents / pharmacology*
Berberine Alkaloids / pharmacology*
Cryptococcus neoformans / drug effects*
Cryptococcus neoformans / genetics
Gene Expression / drug effects*
Gene Expression Regulation, Fungal / drug effects*
Oligonucleotide Array Sequence Analysis

Substances

Antifungal Agents
Berberine Alkaloids

Associated data

GEO/GSE55337

Grants and funding

This work was supported, in part, by the National Research Foundation of Korea Grants (No. 2010-0029117) from MEST (to Y.S.B.) in the Republic of Korea as well as a grant from the Technology Development Program (S2059210) for the use of research facilities funded by the Korea Technology & Information Promotion Agency for Small and Medium Enterprises (to S.U.K.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.