Novel Antifungals by Engineering the AbA NRPS gene

描述(申请人提供)：迫切需要治疗真菌感染、(抗药性)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了重要贡献的化合物。虽然环肽可能是非常有效的药物，但它们是复杂的天然产物，因此，用传统的、基于化学的方法进行优化既困难又昂贵。目前使用的化合物要么是天然化合物，要么是稍加修饰的天然化合物。因此，环肽用于治疗人类疾病的全部潜力还没有被发掘。该项目的总体目标是开发一种具有成本效益的新型抗真菌药物的生产系统。这种分子是一种环肽，尽管它既有效又耐受性好，但它需要通过合成化学以经济有效的方式引入的结构修饰，才能成为市场上的产品。因此，该项目涉及开发方法学和一套遗传工具，允许通过对负责在生产者生物体中合成分子的非核糖体多肽合成酶(NRPS)复合体进行工程来引入所需的修饰。在第一阶段，对编码该NRPS复合体的基因进行了鉴定、克隆、测序和定位。第二阶段将涉及修改这种基因，从而产生的工程化有机体将产生一种具有商品化产品所需特性的药物分子(S)。值得注意的是，(NRPS基因在生产生物体中)的成功工程将允许以合成化学成本的一小部分生产这种药物分子，从而确保一种具有新作用模式的有效、杀伤性抗真菌药物的成功商业化。基因工程药物生产生物体的成功产生将：[1]向对新产品有强烈需求的市场提供一种高效、耐受性良好的药物；[2]满足目前几乎没有治疗选择的不断增长的患者群体的迫切需求；以及[3]为发现新的和改进的疗法的一种新颖的、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。

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.