Regulation of antibiotic biosynthesis in Actinomycetes.

Dbv3 e Dbv4: due regolatori della biosintesi dell’antibiotico glicopeptidico A40926 di Nonomuraea ATCC39727

Production of Antibacterial Compounds from Actinomycetes

Actinomycetes are soil-dwelling Gram-positive bacteria, industrially relevant as producers of a wide range of bioactive secondary metabolites, including many antibiotics of clinical and commercial importance.The understanding of actinomycete biology has been based on extensive studies on the model organism Streptomyces coelicolor over many years and on the availability of its complete genome sequence. This bacterium has an unusual complex developmental cycle that includes programmed cell death phenomena that make this bacterium a multicellular prokaryotic model.Morphological differentiation in S. coelicolor is strictly related to physiological differentiation: indeed the onset of morphologi…

Regulation of physiological differentiation in Nonomuraea sp. ATCC 39727

The Actinomycete Nonomuraea produces the glycopeptide A40926, precursor of dalbavancin, a novel lipoglycopeptide homologous to vancomycin that could be used against emerging resistant Gram-positive bacteria. The A40926 biosynthetic gene cluster (dbv), which consists of 37 genes, encodes two regulators, Dbv3 (LuxR-like) and Dbv4 (StrR-like), as well as the response regulator (Dbv6) and the sensor-kinase (Dbv22) of a putative two-component system. Previous work demonstrated a positive role of Dbv4 in antibiotic production by activating the transcription of 13 dbv genes; up to now no role was assigned to Dbv3, Dbv6 and Dbv22. In addition, an IclR-like protein is thought to be involved in dbv4 …

Regulation of the biosynthesis of the glycopeptide antibiotic A40926 in Nonomuraea ATCC39727

The actinomycete Nonomuraea produces the glycopeptide A40926, precursor of dalbavancin. Dalbavancin is a novel lipoglycopeptide agent against emerging resistant Gram-positive cocci with superior pharmacodynamics properties compared to vancomycin. Chemically, a glycopeptide antibiotic consists of a heptapeptide core constituted by proteinogenic and nonproteinogenic amino acids such as 3,5-dihydroxyphenylglycine (DPG) and 4-hydroxyphenylglycine (HPG). The heptapeptide is assembled by a nonribosomal peptide synthetase and modified by oxidative cross-linking of the electron-rich aromatic side chains, halogenation, sulfation, methylation, acylation, and glycosylation. The A40926 biosynthetic gen…

Two master switch regulators trigger A40926 biosynthesis in Nonomuraea sp. strain ATCC 39727

ABSTRACT The actinomycete Nonomuraea sp. strain ATCC 39727 produces the glycopeptide A40926, the precursor of dalbavancin. Biosynthesis of A40926 is encoded by the dbv gene cluster, which contains 37 protein-coding sequences that participate in antibiotic biosynthesis, regulation, immunity, and export. In addition to the positive regulatory protein Dbv4, the A40926-biosynthetic gene cluster encodes two additional putative regulators, Dbv3 and Dbv6. Independent mutations in these genes, combined with bioassays and liquid chromatography-mass spectrometry (LC-MS) analyses, demonstrated that Dbv3 and Dbv4 are both required for antibiotic production, while inactivation of dbv6 had no effect. In …