Novel Antifungals by Engineering the AbA NRPS gene

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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.