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.
Highlights
Nonomuraea is a genus of so-called “rare” actinomycetes whose potential to produce specialized metabolites is still rather poorly explored.[1,2] Recently sequenced genomes of Nonomuraea species appear to be generally larger than the reference Streptomyces ones
It was recently clarified that N. gerenzanensis produces the Glycopeptide antibiotics (GPAs) in the form of O-acetyl-A40926, but the acetyl group is lost during the alkaline extraction of the antibiotic.[15,16]
The circular chromosome of N. coxensis was found to have a smaller size in comparison to the other two previously published Nonomuraea genomes only 9.07 Mbp compared to 11.85 Mbp in N. gerenzanensis[3] and 13.05 Mbp in Nonomuraea sp
Summary
Nonomuraea is a genus of so-called “rare” actinomycetes whose potential to produce specialized (secondary) metabolites is still rather poorly explored.[1,2] Recently sequenced genomes of Nonomuraea species appear to be generally larger than the reference Streptomyces ones. The most important bioactive metabolite produced by a Nonomuraea species is the type IV8 glycopeptide antibiotic (GPA) A409269 (Figure 1) produced by Nonomuraea gerenzanensis ATCC 39727. A40926 is structurally related to the clinically relevant GPA teicoplanin (Figure 1), produced by Actinoplanes teichomyceticus ATCC 3112110,11 and to ristocetin (Figure 1), previously isolated from numerous Amycolatopsis spp. MJM2582).[12−14] Like teicoplanin, A40926 is produced as a mixture of related compounds (major components are A40926 B and A40926 A factors), which differ in the length and branching of an aliphatic side chain (Figure 1). It was recently clarified that N. gerenzanensis produces the GPA in the form of O-acetyl-A40926 (with an Oacetylated mannose residue), but the acetyl group is lost during the alkaline extraction of the antibiotic.[15,16] Since it was this deacetylated GPA that was initially named A40926, we will refer to it as A40926 hereafter
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