Monday, November 9, 2009
P8

Biosynthetic Mechanism for a Tetramic Acid-containing Antifungal Macrolactam Isolated from the Biocontrol Agent Lysobacter enzymogenes C3

Lili Lou, Yunxuan Xie, Yaoyao Li, and Liangcheng Du. Department of Chemistry, University of Nebraska, 728 Hamilton Hall, Lincoln, NE 68588

Fungal infections have become an increasingly important cause for mortality and morbidity in humans, especially in patients who are immunocompromised or using invasive medical devices and implants. Current therapies emphasize the use of drugs that target ergosterol or cell wall biosynthesis. However, the over reliance on a small set of targets has led to the alarming increase of antifungal drug resistance. Thus, it is an imperative task to continually develop antifungal agents with new modes of action. We have isolated a novel antifungal compound, HSAF (dihydromaltophilin), from the biocontrol agent Lysobacter enzymogenes C3, which is a bacterium effective in protecting crops from fungal diseases. HSAF exhibits activity against a wide range of fungi and shows a novel mode of action through disrupting the polarized growth of filamentous fungi. The chemical structure of HSAF is a tetramic acid-containing macrolactam, in which the two amide functionalities are formed via a hybrid polyketide-peptide (ornithine) mechanism. The novelty in the structure and the mode of action makes it a very interesting target of biosynthetic engineering. In this study, we have constructed a series of mutants of L. enzymogenes C3 including one adenylation (A) domain replaced mutant and four redox gene disrupted mutants. We are also using the heterologously expressed enzymes and the chemically synthesized Orn-SNAC (thioester of N-acetyl cysteamine) and Lys-SNAC to elucidate the mechanism for tetramic acid formation. Our final goals are to determine the molecular mechanism for the biosynthesis of tetramic acid-containing macrolactams and to produce novel analogs through rational biosynthetic engineering.

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