Genomic-Led Discovery of a Novel Glycopeptide Antibiotic by Nonomuraea coxensis 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— 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 Insights into the Distribution and Phylogeny of Glycopeptide Resistance Determinants within the Actinobacteria Phylum

“…Interestingly, this allele was co-localized with a vanRS- like regulatory pair, whereas dbv7 was not. The same situation was observed for N. coxensis DSM 45129—a recently described producer of A40926-like Type IV GPA [ 40 , 68 ]: a cluster-situated dbv7 homologue (almost identical) and a non-cluster-situated vanRSY- triad were identified in its genome. The two other screened genomes of Nonomuraea spp.—the GPA non-producing N. fuscirosea CGMCC 4.7104 and the kistamicin producer Nonomuraea sp.…”

“…In addition , N. gerenzanensis was the first model for studying the role of VanY-like carboxypeptidases in self-resistance [ 38 , 39 ]. Other known GPA producers are Nonomuraea coxensis DSM 45129, recently reported to produce the lipoglycopeptide A50926 [ 40 ], and Nonomuraea sp. ATCC 5507, which produces the type V kistamicin [ 41 ].…”

Heterogeneous A40926 Self-Resistance Profile in Nonomuraea gerenzanensis Population Informs Strain Improvement

“…Nonomuraea is a genus of so-called rare or uncommon filamentous actinomycetes (to distinguish them from the most easy-to-isolate and -to-cultivate Streptomyces spp. ), whose capability to produce specialized (secondary) metabolites is still rather poorly explored [19][20][21]. Probably, the most known Nonomuraea species is the producer of the antibiotic A40926, which was discovered in the late 1980s [1].…”

“…(so far, only three complete assemblies of Nonomuraea spp. genomes are available [20]), although this aspect has not been investigated yet. Further studies are thus needed to unveil the molecular mechanisms underlaying the genetic instability we observed in N. gerenzanensis wild-type population and in its P variant.…”

Genetics Behind the Glycosylation Patterns in the Biosynthesis of Dalbaheptides

“…ATCC 53533) ( Yim et al, 2014a ), pekiskomycin ( pek from Streptomyces sp. WAC1420) ( Thaker et al, 2013 ), keratinimicin (ker from Amycolatopsis keratiniphila NRRL B-24117) ( Xu et al, 2019 ), and A50926 (from Nonomuraea coxensis DSM 45129) ( Yushchuk et al, 2021 ) are also reviewed. Overall, multiple recent findings on dalbaheptide glycosylation updated the overall picture and merit a proper review, outlining what is known and why it is still worthy of further investigations.…”