Biosynthetic and mode of action studies on the nonribosomal peptide antibiotic hormaomycin

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Hormaomycin is a nonribosomal peptide antibiotic isolated from Streptomyces griseoflavus W-384. It contains several unprecedented nonproteinogenic building blocks bearing chlorine, nitro or cyclopropyl moieties. In Streptomyces spp., hormaomycin acts as bacterial hormone by inducing cellular morphogenesis and increasing production titers of antibiotics. In addition, hormaomycin is an antibiotic itself with high potency and selectivity against various coryneform actinomycetes. In previous work, the biosynthetic gene cluster for hormaomycin production was isolated and studied, providing insights into the generation of most building blocks and resulting in the generation of modified analogues and improved production strains. In the proposed project, hormaomycin biosynthesis will be further studied to elucidate the function of previously unassigned genes. By mutasynthesis, the biosynthetic flexibility of the pathway will be further probed, and new analogues will be tested for antibiotic and hormonal activity. Furthermore, the cellular targets for the antibacterial and the possibly interlinked hormonal activity will be investigated by studying regulatory mutants and employing affinity techniques.