Complex Regulatory Networks Governing Production of the Glycopeptide A40926

Abstract

Glycopeptides (GPAs) are an important class of antibiotics, with vancomycin and teicoplanin being used in the last 40 years as drugs of last resort to treat infections caused by Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus. A few new GPAs have since reached the market. One of them is dalbavancin, a derivative of A40926 produced by the actinomycete Nonomuraea sp. ATCC 39727, recently classified as N. gerenzanensis. This review summarizes what we currently know on the multilevel regulatory processes governing production of the glycopeptide A40926 and the different approaches used to increase antibiotic yields. Some nutrients, e.g., valine, l-glutamine and maltodextrin, and some endogenous proteins, e.g., Dbv3, Dbv4 and RpoB^R, have a positive role on A40926 biosynthesis, while other factors, e.g., phosphate, ammonium and Dbv23, have a negative effect. Overall, the results available so far point to a complex regulatory network controlling A40926 in the native producing strain.

Keywords: A40926; LAL; LuxR solo; StrR; dalbavancin; dbv cluster; glycopeptide antibiotics; regulatory genes.

Figure 1

Chemical structures of O-acetyl A40926 and of dalbavancin. Only the component B0 is shown for simplicity. The chemical modification present in dalbavancin is indicated in red type.

Figure 2

Genetic organization of the dbv cluster. The thin black arrows indicate experimentally determined operons. Red triangles indicate experimentally determined Dbv4 binding sites, with the corresponding transcripts as red thick arrows; the thin green arrows represent the transcriptional units controlled by Dbv3. The dbv genes are grouped by functional category as indicated. See also Table 1.

Figure 3

Simplified model of O-acetyl A40926 biosynthesis. Note that the heptapeptide is drawn right (N-terminus) to left (C-terminus), consistent with Figure 1. Cross-links are indicated by blue (C–O–C) or red (C–C) arcs. Sugars are represented as blue hexagons. Refer to Figure 2 and Table 1 for details.

Figure 4

Nutrients, biosynthetic products and proteins regulating A40926 production in Nonomuraea gerenzanensis.