Improved production of A40926 by Nonomuraea sp. through deletion of a pathway-specific acetyltransferase

Abstract

Nonomuraea strain ATCC 39727 produces the glycopeptide A40926, used for manufacturing dalbavancin, currently in advanced clinical trials. From the gene cluster involved in A40926 biosynthesis, a strain deleted in dbv23 was constructed. This mutant can produce only the glycopeptides lacking the O-linked acetyl residue at position 6 of the mannose moiety, while, under identical fermentation conditions, the wild-type strain produces mostly glycopeptides carrying an acetylated mannose. Furthermore, the total amount of glycopeptides produced by the mutant strain was found to be approximately twice that of the wild type. The reduced level of glycopeptides observed in the wild-type strain may be due to an inhibitory effect exerted by the acetylated compound on the biosynthesis of A40926. Indeed, spiking production cultures with > or =1 microg/ml of the acetylated glycopeptide inhibited A40926 production in the mutant strain.