Investigation of Fengycin Mechanism Using Biological, Chemical and Biophysical Tools

控制植物病原体对有效的作物生产至关重要，虽然目前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公司生产的产品Serenade。本品是一种细菌，枯草芽孢杆菌QST713，它产生生物活性脂肽（表面素，iturins和风生素）的混合物。脂肽以植物病原菌的膜为靶点已被证实，大量的研究工作使人们对表面素和iturins的生物合成及其作用机制有了深入的了解。然而，人们对丰霉素知之甚少，丰霉素是细菌产生的第二丰富的脂肽。该项目旨在加深我们对凤霉素抗真菌机制的了解，并通过合成化学和生物合成相结合，产生新的含氟凤霉素衍生物，提高生物活性。这项研究将建立在杜伦（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具有专业知识。该项目将聘请达勒姆的一名PDRA进行合成和生物物理方面的工作，并聘请都柏林的一名博士生进行微生物学/分子生物学实验。此外，博士生（都柏林）将与杜伦大学生物物理科学研究所的同事密切合作，该研究所拥有探索脂肽和膜之间相互作用所需的专业设施。这将为学生带来额外的好处，使他们能够熟练掌握一系列研究工具，从而增加随后就业的机会。这项研究将引起从事天然产物生物合成的学术研究人员、研究风霉素抗真菌作用的研究人员，以及将脂肽作为生物防治剂商业化的公司的极大兴趣。此外，新的氟丰霉素可以在医疗保健部门开辟治疗真菌感染的可能性。

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.