Research in the Li Lab
Our research centers on studying the chemistry and biology of natural products to address major challenges in infectious disease. To combat antibiotic resistance, compounds with novel antimicrobial mechanisms are urgently needed. Natural products are highly successful as life-saving medicines, however, for many natural products, a lack of knowledge about their mode of action has severely limited their utility. We take a multidisciplinary approach to address these challenges, combining natural product chemistry, enzyme chemistry, and molecular microbiology. We elucidate the structures, in vivo mechanisms, and biosynthesis of natural-product antibiotics. In parallel, we characterize the molecular mechanisms by which pathogens infect or damage their hosts. These research areas are described below:
1. Elucidating the mode of action of natural-product antibiotics
Natural products have provided many powerful antimicrobial scaffolds, such as beta-lactams and macrolides. Many natural products with potent antimicrobial activities have been overlooked in part due to a lack of understanding of their mode of action, such as the dithiolopyrrolones (DTPs). DTPs are promising antibiotics because they inhibit a broad spectrum of multidrug-resistant pathogens and exhibit low frequency of resistance. They contain a hetero-bicyclic scaffold and an unusual ene-disulfide, but it was unknown how the unique structure leads to the potent bioactivity. We elucidated the mode of action, redox chemistry, and biosynthesis of the DTP family. Our work identified metal chelation as a promising strategy to overcome antibiotic resistance. Our findings also set the stage for exploring DTPs as antimicrobials and antibiotic adjuvants against multidrug-resistant infections.
2. Identifying pathogen-derived natural-product virulence factors
We aim to understand the roles of pathogen-derived natural products that enable pathogens to infect their hosts (virulence factors). Understanding how pathogens impair host defenses is essential to combating infectious diseases. Pathogens secrete both proteins and small molecules to damage their hosts, but the role of small molecules in virulence is much less understood. Identifying and characterizing small-molecule virulence factors reveals new virulence pathways that could be targeted to control infections. Genome analyses of pathogenic bacteria have uncovered many gene clusters for the biosynthesis of small molecules; the challenge lies in determining the chemical structures of these molecules. We focus on Pseudomonadaceae, an important family of Gram-negative pathogens that infect both plants and humans. We take a multidisciplinary approach to identify novel small-molecule virulence factors to study the chemical interactions between bacteria and their hosts.
3. Deciphering the biosynthesis of natural-product antibiotics
Understanding how bacteria synthesize natural products is essential for identification and engineering of natural products. To augment the discovery and mechanistic studies of natural products, we identify enzymes responsible for their biosynthesis and elucidate the chemistry catalyzed by these enzymes. For example, we study the biosynthesis pathways of natural products comprising nonproteinogenic amino acids (NAAs). NAAs are ubiquitous in bacteria, plants and animals and exhibit antimetabolite, antimicrobial, and agrichemical properties. We characterized the biosynthesis of a unique family of NAAs, the oxyvinylglycines. Our work discovered new enzyme-catalyzed chemistry and generated tools for identifying and engineering of NAAs.
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Latest Li Lab News
November 19, 2021
Congratulations to Jon Patteson, Andrew Putz, Will Simke, Henry Bryant and collaborators from the R. David Britt lab at UC Davis for their paper in Science in which they discovered the biosynthesis of a novel copper containing antibiotic, Fluopsin C, from Pseudomonas aeruginosa. You can read the paper in Science magazine here!
November 12, 2021
Congratulations to Gina Morgan, Drake Crawford, and our collaborators in Jeff Aubé lab for their paper in ACS Chemical Biology outlining the biosynthesis of seven heterocycles produced by the pvf gene cluster from Pseudomonas fluorescens Pf0-1!. You can read the paper in ACS ChemBio here!
September 1, 2021
Congratulations to Torhera Durand for her acceptance into the Chemical Biology Interface Program!
August 27, 2021
Congratulations to Jon Patteson for successfully defending his thesis! Best of Luck at Merck!
August 3, 2021
Congratulations to Rachel (Max) Johnson, Andy Chan, Caylie McGlade, Breanne Hatfield, and our collaborators at the University of Wisconsin-Madison for their paper in JACS examining the mode of action of the hybrid antibiotic thiomarinol! You can read the paper here!
May 1, 2021
Welcome graduate student Torhera Durand to the Li Lab!
January 28, 2021
Congratulations to Ashley, Gina, and Katie for their paper characterizing the secretome regulated by PVF! You can read the paper in ACS Chem Bio.
October 2, 2020
Congratulations Dr. Gina Morgan on successfully defending her thesis! We wish her the best of luck at Oerth Bio.
June 25, 2020
Congratulations to Drake Crawford and Will Simke for obtaining a T32 Biophysics Training Grant Fellowship!
July 14, 2020
Congratulations to Gina for her paper characterizing the N-oxygenase in PVF biosynthesis! You can read the paper in Angewandte here!
May 1, 2020
We welcome our new post-doc, Dr. Qiang Guo, to the lab!
April 25, 2020
Welcome new first year grad students Drake Crawford and Will Simke to the lab!
June 25, 2019
Congratulations to Jon and Adam for their paper discovering the Pseudomonas aeruginosa natural product azabicyclene! You can read the paper in Org Lett here!
June 3, 2019
Congratulations to Gina, Ashley, Kevin, and Savannah for their paper on deciphering the PVF NRPS specificity! You can read the paper in Biochemistry here!
April 15, 2019
We welcome new graduate student Xiaoyan (Betty) to the lab!
April 10, 2019
Congratulations to Andy for successfully defending his thesis! Good luck in Gerry Wright's lab!
March 14, 2019
Congratulations to Ashley for successfully defending her thesis! We look forward to seeing what you'll accomplish in Doug Mitchell's lab!
January 29, 2019
Congratulations to Kevin, Andy, and Erinn for their paper rediscovering the farnesyl transferase-inhibitor Pepticinnamin! You can read the paper in ChemBioChem here!
January 7, 2019
Congratulations to Dr. Erinn O'Neill for successfully defending her thesis! We'll miss you, and good luck at Agilent!
December 7, 2018
Congratulations to Andy and Eli for their paper studying DTP antibiotics chemistry and mode of action! You can read the paper in Chemical Research in Toxicology here!
December 1, 2018
We welcome new graduate student Rachel Johnson (number 2) to the lab!
September 20, 2018
Congratulations to Erinn, Jon, and Eli for their paper discovering bacterial molecules that suppress plant immune response. You can read the paper in P.N.A.S. here! This work was also highlighted on UNC's website
August 7, 2018
Congratulations to Ashley and Gina for their discovery of N-oxygenated compounds produced from the widespread pseudomonas virulence factor pathway. You can read their paper here!
June 20, 2018
We welcome new graduate students Adam and Katie to the lab!
June 13, 2018
Congratulations to Jon for earning a Ralph Bost fellowship!
June 5, 2018
Congratulations to Rachel for earning a Clare Boothe Luce fellowship! You can read more about this competetive award here.