Discovery of broad-spectrum fungicides that block septin-dependent infection processes of pathogenic fungi.

Abstract

Many pathogenic fungi depend on the development of specialized infection structures called appressoria to invade their hosts and cause disease. Impairing the function of fungal infection structures therefore provides a potential means by which diseases could be prevented. In spite of this extraordinary potential, however, relatively few anti-penetrant drugs have been developed to control fungal diseases, of either plants or animals. In the present study, we report the identification of compounds that act specifically to prevent fungal infection. We found that the organization of septin GTPases, which are essential for appressorium-mediated infection in the rice blast fungus Magnaporthe oryzae, requires very-long-chain fatty acids (VLCFAs), which act as mediators of septin organization at membrane interfaces. VLCFAs promote septin recruitment to curved plasma membranes and depletion of VLCFAs prevents septin assembly and host penetration by M. oryzae. We observed that VLCFA biosynthesis inhibitors not only prevent rice blast disease, but also show effective, broad-spectrum fungicidal activity against a wide range of fungal pathogens of maize, wheat and locusts, without affecting their respective hosts. Our findings reveal a mechanism underlying septin-mediated infection structure formation in fungi and provide a class of fungicides to control diverse diseases of plants and animals.

• Authors: Min He, Jia Su, Youpin Xu, Jinhua Chen, Mawsheng Chern, Mingliang Lei, Tuo Qi, Zongkuan Wang, Lauren S Ryder, Bozeng Tang, Míriam Osés-Ruiz, Keke Zhu, Yuyan Cao, Xia Yan, Iris Eisermann, Yuan Luo, Weitao Li, Jing Wang, Junjie Yin, Sin Man Lam, Guoxiong Peng, Xiaofang Sun, Xiaobo Zhu, Bingtian Ma, Jichun Wang, Jiali Liu, Hai Qing, Li Song, Long Wang, Qingqing Hou, Peng Qin, Yan Li, Jing Fan, Deqiang Li, Yuping Wang, Xiue Wang, Ling Jiang, Guanghou Shui, Yuxian Xia, Guoshu Gong, Fu Huang, Wenming Wang, Xianjun Wu, Ping Li, Lihuang Zhu, Shigui Li, Nicholas J Talbot, Xuewei Chen
• Journal: Nature microbiology (Nat Microbiol) Vol. 5 Issue 12 Pg. 1565-1575 (12 2020) ISSN: 2058-5276 [Electronic] England
• PMID: 32958858 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Enzyme Inhibitors
• Fatty Acids
• Fungal Proteins
• Fungicides, Industrial
• Septins

Topics

• Ascomycota (drug effects, enzymology, genetics)
• Enzyme Inhibitors (pharmacology)
• Fatty Acids (metabolism)
• Fungal Proteins (antagonists & inhibitors, genetics, metabolism)
• Fungi (drug effects, enzymology, genetics)
• Fungicides, Industrial (pharmacology)
• Oryza (microbiology)
• Plant Diseases (microbiology)
• Septins (antagonists & inhibitors, genetics, metabolism)