Novel Antifungals by Engineering the AbA NRPS gene

通过改造 AbA NRPS 基因开发新型抗真菌药物

• 批准号: 6831791
• 负责人: Ake P Elhammer
• 金额: $ 16.3万
• 依托单位: AUREOGEN BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2005-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6831791
• 关键词: antifungal agents; antifungal antibiotics; complementary DNA; cyclic peptides; drug design /synthesis /production; enzyme inhibitors; gene expression; genetic library; genetic manipulation; genetic mapping; molecular cloning; nucleic acid sequence

DESCRIPTION (provided by applicant): There is an immediate need for efficient, novel antifungal drugs. The fungus Aureobasidium pullulans produces a cyclic peptide know as Aureobasidin A (AbA) which is a very potent, fungicidal drug that is currently barred from commercialization due to a requirement for modifications involving complex and expensive synthetic chemistry. The overall goal of the project described in this application is to (genetically) engineer A. pullulans to produce cyclic peptides that are, or can be developed into, well-tolerated, potent, broad spectrum antifungal drugs, using no synthetic chemistry or synthetic chemistry limited to a single substitution. Phase I of the project involves the identification, cloning, sequencing and mapping of the gene encoding the non-ribosomal peptide synthetase (NRPS) complex responsible for the synthesis of native AbA in A. pullulans. Determination of the complete NRPS gene sequence will allow identification and mapping of the biosynthetic modules and domains in the complex and thereby elucidation of the assembly sequence of the native compound. This information together with the cloned gene will provide the tools required to carry out the Phase II research plan. Phase II will involve altering the native NRPS complex gene by modifying or switching the biosynthetic modules and domains thereby generating organisms capable of producing novel cyclic peptides requiring minimal chemistry to become potent broad-spectrum antifungal drugs.

描述(由申请人提供)：迫切需要有效的、新型的抗真菌药物。真菌出芽短梗霉产生一种环肽，被称为Aureobasidin A(ABA)，这是一种非常有效的杀菌药物，由于需要涉及复杂而昂贵的合成化学修饰，目前被禁止商业化。本申请中描述的项目的总体目标是(从基因上)改造出芽短梗霉，以生产或可以开发成耐受性良好的、有效的、广谱抗真菌药物的环肽，使用的不是合成化学或仅限于单一取代的合成化学。该项目的第一阶段涉及编码非核糖体多肽合成酶(NRPS)复合体的基因的鉴定、克隆、测序和定位，该复合体负责在出芽短梗霉中合成天然ABA。确定完整的NRPS基因序列将允许鉴定和定位复合体中的生物合成模块和结构域，从而阐明天然化合物的组装序列。这些信息和克隆的基因将提供执行第二阶段研究计划所需的工具。第二阶段将涉及通过修改或交换生物合成模块和结构域来改变天然的NRPS复合体基因，从而产生能够产生新的环肽的生物体，所需最少的化学物质即可成为有效的广谱抗真菌药物。