The combination of high frequencies of infection, high mortality rates, emergence of drug resistance, small number of therapeutic options and a depleted discovery pipeline has resulted in an urgent need for finding new antifungal molecules. Natural products, especially those produced by fungal species as natural antifungal weapons, have been and will continue to play important roles and provide leads for drug discovery. Realizing the immense potential of natural products as antifungal leads, and the prospects of discovering new structures through genome-guided methods, we are proposing a comprehensive and multidisciplinary project to investigate the biosynthesis of fungal-derived 2-pyridone alkaloids, which are complex natural products with potent and selective antifungal activities. We will be particularly focused on a diverse set of enzyme-catalyzed pericyclic reactions that give rise to the polycyclic scaffold important for biological activity. Uncovering these enzymes, followed by detailed investigation of the mechanisms and sequence-activity relationships, will improve our fundamental understanding of enzyme catalysis, and enable biosynthetic engineering approaches to generate natural product analogs, and expand genome mining leads for new antifungals. This multi-PI proposal bring together complementary expertise in three aspects of natural product research: biosynthesis, computational chemistry and synthesis. Together we will address three aims: 1) Investigate SAM-dependent pericyclase using leporin as a model system. 2) Investigate Alder-Ene and dephenylation reactions in pyridoxatin biosynthesis; and 3) Investigate biosynthesis of decalin-containing antifungal 2-pyridone compounds. Insights into the biosynthesis of these molecules will reveal fundamental insights into enzymes that catalyze pericyclic reactions, and provide leads for structure-guided natural product discovery.

Public Health Relevance

Fungal natural products constitute an important part of our antifungal therapy arsenal. Due to ineffectiveness of current drugs and emergence of resistance mechanisms, continued discovery of new antifungal compounds with new modes of actions are needed. We aim to completely understand how nature makes a family of antifungal 2-pyridone natural products, which will reveal new enzymes and enable structure-guided genome mining of new bioactive compounds.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI141481-02
Application #
9823853
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Liu, Baoying
Project Start
2018-11-15
Project End
2023-10-31
Budget Start
2019-11-01
Budget End
2020-10-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095