Production of the Tubulin Destabilizer Disorazol in Sorangium cellulosum : Biosynthetic Machinery and Regulatory Genes

Myxobacteria show a high potential for the production of natural compounds that exhibit a wide variety of antibiotic, antifungal, and cytotoxic activities. 1, 2 The genus Sorangium is of special biotechnological interest because it produces almost half of the secondary metabolites isolated from these microorganisms. We describe a transposon‐mutagenesis approach to identifying the disorazol biosynthetic gene cluster in Sorangium cellulosum So ce12, a producer of multiple natural products. In addition to the highly effective disorazol‐type tubulin destabilizers, 3–5 S. cellulosum So ce12 produces sorangicins, potent eubacterial RNA polymerase inhibitors, 6 bactericidal sorangiolides, and the antifungal chivosazoles. 7, 8 To obtain a transposon library of sufficient size suitable for the identification of the presumed biosynthetic gene clusters, an efficient transformation method was developed. We present here the first electroporation protocol for a strain of the genus Sorangium . The transposon library was screened for disorazol‐negative mutants. This approach led to the identification of the corresponding trans‐acyltransferase core biosynthetic gene cluster together with a region in the chromosome that is likely to be involved in disorazol biosynthesis. A third region in the genome harbors another gene that is presumed to be involved in the regulation of disorazol production. A detailed analysis of the biosynthetic and regulatory genes is presented in this paper.