Integrated omics approach to unveil antifungal bacterial polyynes as acetyl-CoA acetyltransferase inhibitors.

Ching-Chih Lin, Sin Yong Hoo, Li-Ting Ma, Chih Lin, Kai-Fa Huang, Ying-Ning Ho, Chi-Hui Sun, Han-Jung Lee, Pi-Yu Chen, Lin-Jie Shu, Bo-Wei Wang, Wei-Chen Hsu, Tzu-Ping Ko, Yu-Liang Yang

Communications biology 2022 May 12

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Bacterial polyynes are highly active natural products with a broad spectrum of antimicrobial activities. However, their detailed mechanism of action remains unclear. By integrating comparative genomics, transcriptomics, functional genetics, and metabolomics analysis, we identified a unique polyyne resistance gene, masL (encoding acetyl-CoA acetyltransferase), in the biosynthesis gene cluster of antifungal polyynes (massilin A 1, massilin B 2, collimonin C 3, and collimonin D 4) of Massilia sp. YMA4. Crystallographic analysis indicated that bacterial polyynes serve as covalent inhibitors of acetyl-CoA acetyltransferase. Moreover, we confirmed that the bacterial polyynes disrupted cell membrane integrity and inhibited the cell viability of Candida albicans by targeting ERG10, the homolog of MasL. Thus, this study demonstrated that acetyl-CoA acetyltransferase is a potential target for developing antifungal agents. © 2022. The Author(s).

Citation

Ching-Chih Lin, Sin Yong Hoo, Li-Ting Ma, Chih Lin, Kai-Fa Huang, Ying-Ning Ho, Chi-Hui Sun, Han-Jung Lee, Pi-Yu Chen, Lin-Jie Shu, Bo-Wei Wang, Wei-Chen Hsu, Tzu-Ping Ko, Yu-Liang Yang. Integrated omics approach to unveil antifungal bacterial polyynes as acetyl-CoA acetyltransferase inhibitors. Communications biology. 2022 May 12;5(1):454