Genomic-Led Discovery of a Novel Glycopeptide Antibiotic by <i>Nonomuraea coxensis</i> DSM 45129

Abstract

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