Genomic-Led Discovery of a Novel Glycopeptide Antibiotic by DSM 45129.

Glycopeptide antibiotics (GPAs) are last defense line drugs against multidrug-resistant Gram-positive pathogens. Natural GPAs teicoplanin and vancomycin, as well as semisynthetic oritavancin, telavancin, and dalbavancin, are currently approved for clinical use. Although these antibiotics remain efficient, emergence of novel GPA-resistant pathogens is a question of time. Therefore, it is important to investigate the natural variety of GPAs coming from so-called "rare" actinobacteria. Herein we describe a novel GPA producer- DSM 45129. Its sequenced and completely assembled genome harbors a biosynthetic gene cluster (BGC) similar to the BGC of A40926, the natural precursor to dalbavancin. The strain produces a novel GPA, which we propose is an A40926 analogue lacking the carboxyl group on the -acylglucosamine moiety. This structural difference correlates with the absence of -coding for an enzyme responsible for the oxidation of the -acylglucosamine moiety. Introduction of into led to A40926 production in this strain. Finally, we successfully applied and heterologous transcriptional regulators to trigger and improve A50926 production in , making them prospective tools for screening other spp. for GPA production. Our work highlights genus as a still untapped source of novel GPAs.