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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— Nonomuraea coxensis  DSM 45129. Its  de novo  sequenced and completely assembled genome harbors a biosynthetic gene cluster (BGC) similar to the  dbv  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  N -acylglucosamine moiety. This structural difference correlates with the absence of  dbv29 —coding for an enzyme responsible for the oxidation of the  N -acylglucosamine moiety. Introduction of  dbv29  into  N. coxensis  led to A40926 production in this strain. Finally, we successfully applied  dbv3  and  dbv4  heterologous transcriptional regulators to trigger and improve A50926 production in  N. coxensis , making them prospective tools for screening other  Nonomuraea  spp. for GPA production. Our work highlights genus  Nonomuraea  as a still untapped source of novel GPAs.

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