Isolation of the lysolipin gene cluster of Streptomyces tendae Tü 4042

Streptomyces tendae Tü 4042 produces the aromatic polyketide antibiotic lysolipin. Lysolipin has strong antibacterial activity against a variety of multidrug-resistant pathogens. The complete lysolipin biosynthetic gene cluster was isolated and fully sequenced. Within a 42-kb genomic region, 42 genes were identified that code for a type II polyketide synthase ( llpF, E, and D), cyclases ( llpCI–CIII), methyltransferases ( llpMI–MVI), a halogenase ( llpH), an amidotransferase ( llpA), a ferredoxin ( llpK), a transporter ( llpN) and regulatory proteins ( llpRI–RV). In addition, 15 genes encoding enzymes involved in redox modifications of the polyketide precursor molecule ( llpOI–OVIII, ZI–ZIV, U, L, and S) were present in the lysolipin biosynthetic gene cluster. With this high number of oxidoreductases, lysolipin is among the most highly modified aromatic polyketides known to date. The heterologous expression of the cluster in Streptomyces albus led to lysolipin production with a yield comparable to that of wild-type, indicating that all biosynthetic genes were successfully cloned.