Novel Antifungals by Engineering the AbA NRPS gene

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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.