Novel Antifungals by Engineering the AbA NRPS gene

描述（由申请人提供）：目前迫切需要用于治疗真菌感染、（抗生素耐药）细菌感染和癌症的新药。环肽是一类对这些疾病的治疗做出重要贡献的化合物。尽管环肽可以是非常有效的药物，但它们是复杂的天然产物，因此，用常规的基于化学的方法进行优化是困难和昂贵的。目前使用的化合物要么是天然的，要么是经过微小修饰的天然的。因此，尚未探索环肽用于治疗人类疾病的全部潜力。该项目的总体目标是为新型抗真菌药物开发一种具有成本效益的生产系统。该分子是一种环状肽，尽管它既有效又耐受性良好，但它需要结构修饰，而这些结构修饰不能通过合成化学以成本有效的方式引入，以成为可销售的产品。因此，该项目涉及开发方法和一套遗传工具，这将允许通过在生产生物体中对负责分子合成的非核糖体肽合成酶（NRPS）复合物进行工程改造来引入所需的修饰。在第一阶段，编码该NRPS复合物的基因被鉴定、克隆、测序和作图。第二阶段将涉及修改该基因，使得所产生的工程生物体将产生具有可销售产品所需特性的药物分子。值得注意的是，生产生物体中NRPS基因的成功工程改造将允许以合成化学成本的一小部分生产这种药物分子，从而确保具有新作用模式的有效的杀真菌药物的成功商业化。工程药物生产生物体的成功产生将：[1]为对新产品有强烈需求的市场提供有效的，耐受性良好的药物; [2]解决目前治疗选择很少的日益增长的患者群体的迫切需求;（3）为一种新的和潜在的非常强大的基因工程方法提供概念证明和关键工具，以发现新的和改进的治疗学

DESCRIPTION (provided by applicant): There is an immediate need for novel drugs for the treatment of fungal infections, (antibiotics resistant) bacterial infections, and cancer. Cyclic peptides constitute a class of compounds that have made crucial contributions to the treatment of these diseases. Although cyclic peptides can be very efficient drugs, they are complex natural products and as such, difficult and expensive to optimize with conventional, chemistry- based methodologies. Currently used compounds are either native or native with minor modifications. Hence, the full potential of cyclic peptides for the treatment of human diseases has not been explored. The overall goal of the project is to develop a cost-effective production system for a novel antifungal drug. This molecule is a cyclic peptide and although it is both potent and well-tolerated, it requires structural modifications that cannot be introduced in a cost-effective manner by synthetic chemistry, to become a marketable product. Thus, the project involves development of methodologies and a set of genetic tools that will allow introduction of the required modifications by engineering of the non-ribosomal peptide synthetase (NRPS) complex responsible for synthesis of the molecule, in the producer organism. In Phase I, the gene encoding this NRPS complex was identified, cloned, sequenced and mapped. Phase II will involve modifying this gene such that the resulting, engineered organism will produce a drug molecule(s) with the properties required for a marketable product. Notably, successful engineering of the (NRPS gene in the) producer organism will allow production of this drug molecule at a fraction of the cost of synthetic chemistry thereby ensuring the successful commercialization of a potent, cidal antifungal drug with a novel mode of action. Successful generation of the engineered drug producer organism will: [1] provide an efficient, well-tolerated drug to a market with a strong demand for new products; [2] address a very immediate need from a growing patient population which currently have very few treatment options; and [3] provide proof of concept and critical tools for a novel and potentially very powerful genetic engineering approach to the discovery of new and improved therapeutics.