LAntibiotic Production: Technology, Optimization and improved Process

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The focus of this project is to develop an economically viable production process for the lantibiotic NAI-107, a new antibiotic with the potential to treat life-threatening infections caused by multi-drug resistant Gram-positive pathogens. NAI-107 is produced by fermentation of the actinomycete Microbispora sp.

A challenge in advancing a new antibiotic into clinical development is to devise a production process that will deliver a high quality compound at reasonable yields. This is particularly relevant for NAI-107 since no lantibiotics are industrially produced as drugs for human use and there are no examples of industrial use of Microbispora.

The development of a robust and economically feasible production process for NAI-107 requires the integration of basic knowledge of the physiology of the strain which can be best obtained by a combination of classical and post-genomic approaches (proteome/transcriptome), with a detailed knowledge of the production process and its scalability to industrial level. This will be achieved by flux analyses and 2D-maps for discovering primary metabolism proteins up-regulated during antibiotic production.

Combined with a study of other limiting steps, such as precursor uptake, product excretion and the intrinsic resistance of the producing strain, and with analysis of the transcriptional regulation of the NAI-107 biosynthetic genes, bottlenecks in production will be identified and bypassed by metabolic engineering leading to an optimized metabolic pathway for the production of this life-saving antibiotic and an efficient production process utilizing a high producing strain, an improved production medium and an efficient recovery process.

NAICONS, an SME participating in the project and acting as coordinator, has advanced NAI-107 to late preclinical development, and reached an agreement with Sentinella Pharmaceuticals Inc. for its further development. The compound is currently ready to undergo formal toxicology studies before Phase I clinical trials.