Cross-Talking of Pathway-Specific Regulators in Glycopeptide Antibiotics (Teicoplanin and A40926) Production

Teicoplanin and A40926 (natural precursor of dalbavancin) are clinically relevant glycopeptide antibiotics (GPAs) produced by NRRL B-16726 and ATCC 39727. Their biosynthetic enzymes are coded within large biosynthetic gene clusters (BGCs), named for teicoplanin and for A40926, whose expression is strictly regulated by pathway-specific transcriptional regulators (PSRs), coded by cluster-situated regulatory genes (CSRGs). Herein, we investigated the "cross-talk" between the CSRGs from and , through the analysis of GPA production levels in and strains, with knockouts of CSRGs cross-complemented by the expression of heterologous CSRGs. We demonstrated that Tei15* and Dbv4 StrR-like PSRs, although orthologous, were not completely interchangeable: and were only partially able or unable to cross-complement knocked out in and . knocked out in , implying that the DNA-binding properties of these PSRs are more different than it was believed before. At the same time, the unrelated LuxR-like PSRs Tei16* and Dbv3 were able to cross-complement corresponding knocked out in and knocked out in . Moreover, the heterologous expression of in led to a significant increase in teicoplanin production. Although the molecular background of these events merits further investigations, our results contribute to a deeper understanding of GPA biosynthesis regulation and offer novel biotechnological tools to improve their production.