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

霍尔霉素是从灰黄链霉菌W-384中分离得到的一种非核糖体多肽抗生素。它含有几个史无前例的非蛋白生成成分，含有氯、硝基或环丙基。在链霉菌中，红霉素通过诱导细胞形态发生和增加抗生素的产量而起到细菌激素的作用。此外，红霉素本身是一种对各种棒状放线菌具有高效和选择性的抗生素。在以前的工作中，分离和研究了用于生产霍毛霉素的生物合成基因簇，为大多数构建块的产生提供了见解，并导致了修饰类似物和改良生产菌株的产生。在拟议的项目中，将进一步研究红霉素的生物合成，以阐明以前未分配的基因的功能。通过突变合成，将进一步探讨该途径的生物合成灵活性，并将测试新的类似物的抗生素和激素活性。此外，将通过研究调节突变和使用亲和力技术来研究抗菌和可能相互关联的激素活性的细胞靶点。

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.