Biosynthesis of merochlorins - A novel class of highly active halogenated polyketide antibiotics from marine Streptomyces sp.

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Marine microbes have recently emerged as an important source of chemically distinct antimicrobial agents with potential for medical applications in the treatment of infectious diseases or cancer. A plenitude of such compounds is synthesized by use of aromatic polyketide frameworks undergoing dedicated oxidative tailoring reactions, which strongly contribute to the compounds potent biological activities. Recently, some marine Streptomyces sp. were shown to produce a unique class of highly active, chlorinated polyketide antibiotics (merochlorins) that may be derived from prenylated and halogenated tetrahydroxynaphthalene precursors. Vanadium-dependent chloroperoxidases presumably catalyze the crucial cyclization and ring-expansion steps. This study aims at investigating the biosynthesis of the novel merochlorin antibiotics. The main focus of the project lies on the exploration of the biochemical steps leading to the modified tetrahydroxynaphthalene precursors, along with the examination of the proposed unprecedented chloroperoxidase-catalyzed macrocyclization and ring-formation/expansion reactions. Systematic gene inactivation, in vitro studies of heterologous proteins and their catalytic features, site-directed mutagenesis, and X-ray crystallography will be applied to functionally assign and characterize involved proteins and to expose the underlying reaction mechanisms, with the ultimate goal to establish biosynthetic pipelines for biological evaluation in antibiotic screens.