Investigation of Fengycin Mechanism Using Biological, Chemical and Biophysical Tools

控制植物病原体对于有效的作物生产至关重要，虽然目前可用于消除真菌病原体的许多产品是合成化学品，但也有一些生物防治产品(“生物杀菌剂”)。其中之一是由AgraQuest公司制造的产品Serenade。该产品是一种细菌，枯草芽孢杆菌QST713，它产生一种具有生物活性的脂肽(表面活性脂肽、淫羊藿苷和凤尾菌素)的混合物。已有的研究表明，脂肽以植物病原体的膜为靶标，大量的研究工作使人们能够深入了解表面蛋白和iturins的生物合成和作用机制。然而，人们对风霉素知之甚少，它是细菌产生的第二丰富的脂肽。本项目旨在加深我们对风霉素抗真菌机制的认识，并通过合成化学和生物合成相结合的方法来合成新的具有更高生物活性的氟化风霉素衍生物。这项研究将建立在达勒姆(Steven Cobb)和都柏林(Cormac Murphy)的研究人员之间非常成功的合作基础上，他们分别在合成氟化学和微生物生物合成方面拥有专业知识。该项目将在达勒姆雇用一名PDRA进行合成和生物物理方面的工作，并在都柏林雇用一名博士生进行微生物学/分子生物学实验。此外，这位博士生(都柏林)将与达勒姆生物物理科学研究所的同事密切合作，该研究所拥有必要的专业设施来探索脂肽和膜之间的相互作用。这将为学生获得一系列研究工具的熟练程度带来额外的好处，这些工具将增加后续就业的机会。这项研究将对参与天然产物生物合成的学术研究人员和那些研究丰菌素的抗真菌作用的人，以及将脂肽作为生防剂商业化的公司产生重大兴趣。此外，新的氟风菌素可能会在医疗保健部门为治疗真菌感染打开可能性。

Control of plant pathogens is vital for effective crop production and whilst many products currently available for the elimination of fungal pathogens are synthetic chemicals, there are some biological control products ('biofungicides'). One of these is the product Serenade, which is manufactured by the company AgraQuest. This product is a bacterium, Bacillus subtilis QST713, which produces a mixture of bioactive lipopeptides (surfactins, iturins and fengycins). It has been established that the lipopeptides target the membranes of phytopathogens and considerable research effort has enabled a deep understanding of both the biosynthesis and mechanism of action of surfactins and iturins. However, much less is known about fengycin, which is the second most abundant lipopeptide produced by the bacterium. This project aims to deepen our knowledge of the anti-fungal mechanism of fengycin and to generate new fluorinated fengycin derivatives, via a combination of synthetic chemistry and biosynthesis, with improved bioactivity. The research will build on a highly successful collaboration between researchers in Durham (Steven Cobb) and Dublin (Cormac Murphy) who have expertise in synthetic fluorine chemistry and microbial biosynthesis, respectively. The project will employ a PDRA in Durham for the synthetic and biophysical aspects of the work and a PhD student in Dublin to conduct the microbiology/molecular biology experiments. In addition the PhD student (Dublin) will work closely with colleagues in Durham's Biophysical Science Institute, which has the specialist facilities necessary to probe the interaction between the lipopeptide and membrane. This will have the added benefit for the student to gain proficiency in a range of research tools that will boost chances of subsequent employment. The research will be of significant interest to academic researchers involved in natural product biosynthesis and those investigating the antifungal action of fengycins, and to companies that commercialise lipopeptides as biocontrol agents. Furthermore, the new fluorofengycins could open possibilities in the healthcare sector for the treatment of fungal infections.