Education

• Postdoc. University of California, Davis
• Ph.D., The Royal Vet and Ag University, Denmark
• M.S., The Chinese Academy of Sciences
• B.S., Yunnan University, China

Research Interests

Our research focuses on the biosynthetic mechanisms and metabolic engineering of novel antifungal and anti-MRSA antibiotics from underexplored bacteria, as well as mycotoxins and other bioactive natural products from plant pathogenic fungi and endophytes.

Current Research

1. Investigating the molecular mechanisms underlying the biosynthesis of novel antibiotics, mycotoxins, and other bioactive natural products.
2. Discovering new antibiotics and signaling molecules from Lysobacter bacteria, endophytic fungi, and other underexplored sources.
3. Engineering metabolic pathways to enhance the production of valuable natural products.

Research in the Du group is at the interface of chemistry and biology, focusing on understanding how microorganisms biosynthesize structurally complex and biologically active natural products. Our ultimate goal is to harness this knowledge for the development of new bioactive compounds through biosynthetic approaches. Our research integrates expertise from chemistry, biochemistry, chemical biology, and synthetic biology. Currently, we are pursuing two major projects aimed at advancing antibiotic discovery and metabolic pathway engineering.

New antibiotics from underexplored microorganisms

Lysobacter is a genus of environmental bacteria first classified in 1978, with several species recognized as prolific producers of bioactive natural products and emerging biocontrol agents (Nat. Prod. Rep. 2012; Nat. Prod. Rep. 2022). From the biocontrol agent Lysobacter enzymogenes, we have isolated HSAF, a potent antifungal compound with a novel mode of action (Mol. Biol. Cell 2006; RSC Adv. 2016; Biochim. Biophys. Acta 2016) and unique structural features distinct from existing fungicides and antifungal drugs (Antimicrob. Agents Chemother. 2007). We identified the genes responsible for HSAF biosynthesis and uncovered a previously unrecognized hybrid polyketide-peptide biosynthetic mechanism (J. Am. Chem. Soc. 2011; Biochemistry 2012; Angew. Chem. Int. Ed. 2014, 2018; Biochemistry 2020).      

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We have isolated three classes of potent anti-MRSA cyclic lipodepsipeptides and identified their biosynthetic gene clusters (Antimicrob. Agents Chemother. 2011; ACS Synth. Biol. 2013, 2018, 2020; Org. Lett. 2019). These cyclic lipopeptides are structurally distinct from daptomycin, a clinically used antibiotic effective against Gram-positive pathogens, including MRSA and vancomycin-resistant enterococci (VRE).

Through genome mining, we discovered various bioactive natural products, including the broad-spectrum antibiotic phenazines, and identified an unprecedented Baeyer-Villiger-like flavin enzyme responsible for phenazine N-oxidation (Org. Lett. 2016, 2017; ACS Chem. Biol. 2018).

Despite its promise, Lysobacter has remained challenging to manipulate genetically. To address this, we have developed novel tools for activating silent biosynthetic genes and advancing synthetic biology in Lysobacter, enabling improved compound yields and unveiling intricate regulatory mechanisms (Appl. Environ. Microbiol. 2017, 2021; ACS Chem. Biol. 2021; J. Agric. Food Chem. 2023, 2025).

Mycotoxins from Food-Borne Molds

Our research aims to develop innovative strategies for reducing or eliminating mycotoxins in food and feed. We have focused on fumonisins, a group of fungal polyketides, to understand their biosynthetic mechanisms. This knowledge will facilitate rational approaches to controlling mycotoxin contamination.

Fumonisins rank among the five most economically significant mycotoxins in agriculture and the food industry (Biopolymers 2010). They are produced by the pathogenic fungus Fusarium verticillioides, a widespread contaminant of corn and maize-derived food and feed. Consumption of fumonisin-contaminated corn leads to fatal diseases in livestock and poses a cancer risk to humans.

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To investigate fumonisin biosynthesis, we developed a genetic system capable of precisely modifying biosynthetic genes in filamentous fungi. Using this system, we created gene-specific mutants, identified biosynthetic intermediates, and established a biosynthetic pathway (J. Am. Chem. Soc. 2007). Additionally, we leveraged E. coli and Saccharomyces cerevisiae as heterologous hosts to express and study fungal genes (Biochemistry 2006).

Our studies uncovered an unprecedented PLP-dependent polyketide chain-releasing mechanism, in which a discrete 2-oxoamine synthase catalyzes a decarboxylative condensation between L-alanine and acyl-S-ACP (J. Am. Chem. Soc. 2009). This reaction facilitates polyketide chain termination and offloading while simultaneously introducing a new carbon-carbon bond and an amino group. Unlike the thioesterase/cyclase-mediated chain release observed in bacterial and other fungal polyketide biosynthesis, this mechanism represents a novel paradigm in fungal secondary metabolism (Nat. Prod. Rep. 2010).

For more information, please visit the Du Research Group Homepage.

Selected Publications

Li X, Pan C, Wang H, Shen Y, Li Y, and Du L. 2025. Heterologous production of phenazines in the biocontrol agent Lysobacter enzymogenes C3. Journal of Agricultural and Food Chemistry 73: 1345-1355. pdf

Zhang F, Liu J, Jiang L, Zheng Y, Yu L, and Du L. 2024. Production of the siderophore lysochelin in rich media through maltose-promoted high-density growth of Lysobacter sp. 3655. Frontiers in Microbiology 15:1433983. pdf

Miller A, Li S, Eichhorn CD, Zheng Y, and Du L. 2023. Identification and biosynthetic study of the siderophore lysochelin in the biocontrol Agent Lysobacter enzymogenes. Journal of Agricultural and Food Chemistry 71: 7418-7426. pdf

Han W, Zhai Y, Zhang R, Gong X, Li J, Xu G, Lei X, Du L, and Gao J. 2023. Tricrilactones A−H, potent antiosteoporosis macrolides with distinctive ring skeletons from Trichocladium crispatum, an alpine moss-associated fungus. Angewandte Chemie International Edition 62: e202300773. pdf.

Yue H, Miller A, Khetrapal V, Jayasekera V, Wright S, and Du L. 2022. Biosynthesis, regulation, and engineering of natural products from Lysobacter. Natural Product Reports 39: 842 – 874. pdf

Yue H, Jiang J, Taylor A, Leite A, Dodds E, and Du L. 2021. Outer membrane vesicles-mediated co-delivery of the antifungal HSAF metabolites and lytic polysaccharide monooxygenase in the predatory Lysobacter enzymogenes. ACS Chemical Biology 16: 1079-1089. pdf

Yu L, Li H, Zhou Z, Liu F, and Du L. 2021. An antifungal polycyclic tetramate macrolactam HSAF is a novel oxidative stress modulator in Lysobacter enzymogenes. Applied and Environmental Microbiology 87: e03105-20. pdf

Yu L, Du F, Chen X, Zheng Y, Morton M, Liu F, and Du L. 2020. Identification of the biosynthetic gene cluster for the anti-MRSA lysocins through gene cluster activation using strong promoters of housekeeping genes and production of new analogs in Lysobacter sp. 3655. ACS Synthetic Biology 9: 1989-1997. pdf

Sang M, Wang H, Shen Y, Rodrigues de Almeida N, Conda-Sheridan M, Li S, Li Y, and Du L. 2019. Identification of an anti-MRSA cyclic lipodepsipeptide, WBP-29479A1, by genome mining of Lysobacter antibioticus. Organic Letters 21: 6432-6436. pdf.

Li X, Wang H, Shen Y, Li Y, and Du L. 2019. OX4 is an NADPH-dependent dehydrogenase catalyzing an extended Michael addition reaction to form the six-membered ring in the antifungal HSAF. Biochemistry 58: 5245−5248. pdf

Li Y, Wang H, Liu Y, Jiao Y, Li S, Shen Y, and Du L. 2018. Biosynthesis of the polycyclic system in the antifungal HSAF and analogues from Lysobacter enzymogenes. Angewandte Chemie International Edition 57: 6221-6225. pdf

Jiang J, Guiza-Beltran D, Schacht A, Wright S, Zhang L, and Du L. 2018. Functional and structural analysis of phenazine O-methyltransferase LaPhzM from Lysobacter antibioticus OH13 and one-pot enzymatic synthesis of the antibiotic myxin. ACS Chemical Biology 13: 1003-1012. pdf.

Yu L, Su W, Fey P, Liu F, and Du L. 2018. Yield improvement of the anti-MRSA antibiotics WAP-8294A by CRISPR/dCas9 combined with refactoring self-protection genes in Lysobacter enzymogenes OH11. ACS Synthetic Biology 7: 258−266. pdf.

Li S, Wu X, L Zhang, Shen Y, and Du L. 2017. Activation of a cryptic gene cluster in Lysobacter enzymogenes revealed a module/domain portable mechanism of nonribosomal peptide synthetases in the biosynthesis of pyrrolopyrazines. Organic Letters 19: 5010−5013. pdf.

Han Y, Wang Y, Yu Y, Chen H, Shen Y, and Du L. 2017. Indole-induced reversion of intrinsic multi-antibiotic resistance in Lysobacter enzymogenes. Applied and Environmental Microbiology 83:e00995-17. pdf.

Zhao Y, Qian G, Ye Y, Wright S, Chen H, Shen Y, Liu F, and Du L. 2016. Heterocyclic aromatic N-oxidation in the biosynthesis of phenazine antibiotics from Lysobacter antibioticus. Organic Letters 18: 2495-2498. pdf

Wang M, Zhang W, Xu W, Shen Y, and Du L. 2016. Optimization of genome shuffling for high yield production of the antitumor deacetylmycoepoxydiene in an endophytic fungus of mangrove plants. Applied Microbiology and Biotechnology 100: 7491–7498. pdf

Han Y, Wang Y, Tombosa S, Wright S, Huffman J, Yuen G, Qian G, Liu F, Shen Y, and Du L. 2015. Identification of a small molecule signaling factor that regulates the biosynthesis of the antifungal polycyclic tetramate macrolactam HSAF in Lysobacter enzymogenes. Applied Microbiology and Biotechnology 99: 801-811. pdf
 

Li Y, Chen H, Ding Y, Xie Y, Wang H, Cerny RL, Shen Y, and Du L. 2014. Iterative assembly of two separate polyketide chains by the same single-module bacterial polyketide synthase in the biosynthesis of HSAF. Angewandte Chemie International Edition 53: 7524-7530. pdf

Wang Y, Qian G, Liu F, Li Y-Z, Shen Y, and Du L. 2013. Facile method for site-specific gene integration in Lysobacter enzymogenes for yield improvement of the anti-MRSA antibiotics WAP-8294A and the antifungal antibiotic HSAF. ACS Synthetic Biology 2: 670-678. pdf

Zhao PJ, Yang YL, Du L, Liu JK, and Zeng Y. 2013. Elucidating the biosynthetic pathway for vibralactone: A pancreatic lipase inhibitor with a fused bicyclic ß-lactone. Angewandte Chemie International Edition 52: 1-6. pdf

Xie Y, Wright S, Shen Y, and Du L. 2012. Bioactive natural products from Lysobacter. Natural Product Reports 29: 1277-1287. pdf

Lou L, Chen H, Cerny RL, Li Y, Shen Y, and Du L. 2012. Unusual activities of the thioesterase domain for the biosynthesis of the polycyclic tetramate macrolactam HSAF in Lysobacter enzymogenes C3. Biochemistry 51, 4-6. pdf. (Highlighted on Biochemistry website, January, 2012).

Zhang W, Li Y, Qian G, Wang Y, Chen H, Li Y-Z, Liu F, Shen Y, and Du L. 2011. Identification and characterization of the anti-Methicillin-Resistant Staphylococcus aureus WAP-8294A2 biosynthetic gene cluster from Lysobacter enzymogenes OH11. Antimicrobial Agents and Chemotherapy 55: 5581-5589. pdf.

Lou L, Qian G, Xie Y, Hang J, Chen H, Zaleta-Rivera K, Li Y, Shen Y, Dussault PH, Liu F, and Du L. 2011. Biosynthesis of HSAF, a tetramic acid-containing macrolactam from Lysobacter enzymogenes. Journal of the American Chemical Society 133: 643-645. pdf.

Du L and Lou L. 2010. PKSs and NRPSs release mechanisms. Natural Product Reports 27: 255-278. pdf.

Gerber R, Lou L, and Du L. 2009. A PLP-dependent polyketide chain releasing mechanism in the biosynthesis of mycotoxin fumonisins in Fusarium verticillioides. Journal of the American Chemical Society 131: 3148-3149. pdf.  (Highlighted on JACS website, March, 2009).

Zhu X, Yu F, Li X-C, and Du L. 2007. Production of dihydroisocoumarins in Fusarium verticillioides by swapping the ketosynthase domain of the fungal iterative modular polyketide synthase Fum1p with that of lovastatin diketide synthase. Journal of the American Chemical Society 129: 36-37. pdf.

Yu F, Zaleta-Rivera K, Zhu X, Huffman J, Millet J, Harris SD, Yuen G, Li X, and Du L. 2007. Structure and biosynthesis of HSAF, a broad spectrum antimycotic with a novel mode of action. Antimicrobial Agents and Chemotherapy 51: 64-72. pdf. Cited by Faculty of 1000 Biology (Evaluated by D. Newman, NIH, March 8, 2007) pdf.

Zaleta-Rivera K, Xu C, Yu F, Butchko RAE, Proctor RH, Lara MEH, Raza A, Dussault PH, and Du L. 2006. A bidomain nonribosomal peptide synthetase encoded by FUM14 catalyzes the formation of tricarballylic esters in the biosynthesis of fumonisins. Biochemistry 45: 2561-2569. pdf

Citations and h-index

Complete list of publications