Phosphopantetheinyl transferase inhibition and secondary metabolism.

摘要: Efforts to isolate carrier protein-mediated synthases from natural product-producing organisms using reporter-linked post-translational modification have been complicated by the efficiency of endogenous process. To address this issue, we chose target phosphopantetheinyl transferases (PPTases) for inhibitor design facilitate product synthase isolation through a chemical genetics approach. Herein validate secondary metabolism-associated PPTase probe development. We synthesized and evaluated panel compounds based on anthranilate 4H-oxazol-5-one pharmacophore previously described attenuate activity within bacterial cultures. Through use new high-throughput Forster resonance energy transfer assay, demonstrated that these exclusively inhibit fatty acid synthase-specific PPTases. In vivo, lead compound selective antibiotic in Bacillus subtilis model. Further evaluation enhances actinorhodin production Streptomyces coelicolor, revealing ability class molecules stimulate precocious metabolite production.