TY - JOUR
T1 - Resistance Gene-Guided Discovery of a Fungal Spirotetramate as an Acetolactate Synthase Inhibitor
AU - Chan, Tsz Ki
AU - Wei, Xingxing
AU - Ma, Li
AU - Wang, Hang
AU - Liao, Pan
AU - Matsuda, Yudai
N1 - We thank Prof. Katsuya Gomi (Tohoku University) and Profs. Katsuhiko Kitamoto and Jun-ichi Maruyama (University of Tokyo) for the expression vectors and fungal strain. We are also grateful to Dr. Kwok Chung Law (City University of Hong Kong) for the NMR spectra acquisition and Dr. Shek Man Yiu (City University of Hong Kong) for X-ray diffraction data collection and analysis. We also thank Prof. Jeroen S. Dickschat (University of Bonn) for helpful discussions regarding the reaction mechanisms. This work was carried out using the computational facilities, CityUHK Burgundy, managed and provided by the Computing Services Centre at City University of Hong Kong (https://www.cityu.edu.hk/). The plasmid pAT426 was provided by the National BioResource Project (NBRP) yeast, Japan. This work was supported by General Research Fund grants from the Research Grants Council of Hong Kong (RGC) (Project Nos. 11309022 and 11301724 to Y.M.), the Research Enhancement Grant from City University of Hong Kong (Project No. 7020157 to Y.M.), Early Career Scheme grant from the RGC (Project No. 22100923 to P.L.), the NSFC/RGC Joint Research Scheme (Project No. N_HKBU201/23 to P.L.), and Areas of Excellence Scheme from the RGC (AoE/M-402/25-N).
Publisher Copyright:
© 2025 The Authors. Published by American Chemical Society
PY - 2025/11/12
Y1 - 2025/11/12
N2 - Biosynthetic gene clusters (BGCs) of bioactive natural products occasionally encode resistant versions of the proteins they inhibit, offering opportunities for resistance gene-guided genome mining to uncover natural products with predictable modes of action. In this study, we developed a genome mining tool designed to identify fungal BGCs harboring putative resistance genes. Applying this tool to approximately 2500 fungal genomes, we identified a BGC designated as the pts cluster, which encodes an acetolactate synthase (ALS) homologue. Functional characterization of the pts cluster resulted in the identification of pterrespiramide A (1), featuring unique spirotetramate and cis-decalin moieties. Consistent with the predicted activity, 1 was confirmed as an ALS inhibitor and exhibited both antifungal and herbicidal activities. This study illuminates the potential of resistance gene-guided genome mining as a powerful strategy for accelerating the discovery of previously undescribed bioactive natural products.
AB - Biosynthetic gene clusters (BGCs) of bioactive natural products occasionally encode resistant versions of the proteins they inhibit, offering opportunities for resistance gene-guided genome mining to uncover natural products with predictable modes of action. In this study, we developed a genome mining tool designed to identify fungal BGCs harboring putative resistance genes. Applying this tool to approximately 2500 fungal genomes, we identified a BGC designated as the pts cluster, which encodes an acetolactate synthase (ALS) homologue. Functional characterization of the pts cluster resulted in the identification of pterrespiramide A (1), featuring unique spirotetramate and cis-decalin moieties. Consistent with the predicted activity, 1 was confirmed as an ALS inhibitor and exhibited both antifungal and herbicidal activities. This study illuminates the potential of resistance gene-guided genome mining as a powerful strategy for accelerating the discovery of previously undescribed bioactive natural products.
UR - https://www.scopus.com/pages/publications/105021398627
U2 - 10.1021/jacs.5c16272
DO - 10.1021/jacs.5c16272
M3 - Journal article
C2 - 41148120
AN - SCOPUS:105021398627
SN - 0002-7863
VL - 147
SP - 42100
EP - 42109
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 45
ER -