title: A vanillin derivative causes mitochondrial dysfunction and triggers oxidative stress in Cryptococcus neoformans.
abstract: Vanillin is a well-known food and cosmetic additive and has antioxidant and antimutagenic properties. It has also been suggested to have antifungal activity against major human pathogenic fungi, although it is not very effective. In this study, the antifungal activities of vanillin and 33 vanillin derivatives against the human fungal pathogen Cryptococcus neoformans, the main pathogen of cryptococcal meningitis in immunocompromised patients, were investigated. We found a structural correlation between the vanillin derivatives and antifungal activity, showing that the hydroxyl or alkoxy group is more advantageous than the halogenated or nitrated group in benzaldehyde. Among the vanillin derivatives with a hydroxyl or alkoxy group, o-vanillin and o-ethyl vanillin showed the highest antifungal activity against C. neoformans. o-Vanillin was further studied to understand the mechanism of antifungal action. We compared the transcriptome of C. neoformans cells untreated or treated with o-vanillin by using RNA sequencing and found that the compound caused mitochondrial dysfunction and triggered oxidative stress. These antifungal mechanisms of o-vanillin were experimentally confirmed by the significantly reduced growth of the mutants lacking the genes involved in mitochondrial functions and oxidative stress response.
authors.affiliation: Chemical Safety Division, National Academy of Agriculture Science, Rural Development of Administration, Suwon, Republic of Korea.
authors.forename: Jin Hyo
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Systems Biotechnology, Chung-Ang University, Anseong, Republic of Korea.
authors.forename: Han-Ok
authors.initials: HO
authors.lastname: Lee
authors.affiliation: ChunLab, Inc., Seoul National University, Seoul, Republic of Korea.
authors.forename: Yong-Joon
authors.initials: YJ
authors.lastname: Cho
authors.affiliation: Department of Systems Biotechnology, Chung-Ang University, Anseong, Republic of Korea.
authors.forename: Jeongmi
authors.initials: J
authors.lastname: Kim
authors.affiliation: ChunLab, Inc., Seoul National University, Seoul, Republic of Korea ; School of Biological Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: Jongsik
authors.initials: J
authors.lastname: Chun
authors.affiliation: Research Division for Biotechnology, Korea Atomic Energy Research Institute, Jeongup, Republic of Korea.
authors.forename: Jaehyuk
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Chemistry, KAIST, Daejeon, Republic of Korea.
authors.forename: Younghoon
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Systems Biotechnology, Chung-Ang University, Anseong, Republic of Korea.
authors.forename: Won Hee
authors.initials: WH
authors.lastname: Jung
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001547:Benzaldehydes / Q000737:chemistry* / Q000494:pharmacology*; D003455:Cryptococcus neoformans / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009154:Mutation; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D059467:Transcriptome / Q000187:drug effects
chemical_list: D000935:Antifungal Agents; D001547:Benzaldehydes; C100058:vanillin