Heterologous Expression and Engineering Studies of Labyrinthopeptins, Class III Lantibiotics from Actinomadura namibiensis

SummaryLabyrinthopeptins are class III lantibiotics produced by the actinomycete Actinomadura namibiensis. The most characteristic structural feature is the posttranslationally installed triamino triacid labionin with a quaternary α-carbon. In addition to the unique structure, labyrinthopeptin A2 possess remarkable antiviral and antiallodynic biological activities. To harness the substrate tolerance of the biosynthetic machinery, we developed an efficient system for the generation of labyrinthopeptin analogs. Streptomyces lividans was used as a heterologous host since the natural producer Actinomadura namibiensis remained genetically intractable. Generation of a library of 39 mutants allowed identification of variable and invariable regions in the labyrinthopeptin structures. Additional data on the flexibility of the biosynthetic machinery were provided by in vitro experiments. This study is detailed investigation on the potential to generate analogs of class III lantibiotics by genetic engineering.

Graphical AbstractFigure optionsDownload high-quality image (183 K)Download as PowerPoint slideHighlights
► Heterologous expression of a class III lantibiotic gene cluster in S. lividans and S. albus
► Leader peptide adaptation for proteolytic processing in the S. lividans host
► Development of an efficient expression system for production of labyrinthopeptin variants
► Identification of variable regions in labyrinthopeptins and generation of analogs