ABSTRACT
Hybrid genome-mining/15N-NMR was used to target compounds containing piperazate (Piz) residues, leading to the discovery of caveamides A (1) and B (2) from Streptomyces sp. strain BE230, isolated from New Rankin Cave (Missouri). Caveamides are highly dynamic molecules containing an unprecedented ß-ketoamide polyketide fragment, two Piz residues, and a new N-methyl-cyclohexenylalanine residue. Caveamide B (2) exhibited nanomolar cytotoxicity against several cancer cell lines and nanomolar antimicrobial activity against MRSA and E. coli.
Subject(s)
Escherichia coli , Methicillin-Resistant Staphylococcus aureus , Streptomyces , Humans , Molecular Structure , Streptomyces/chemistry , Escherichia coli/drug effects , Methicillin-Resistant Staphylococcus aureus/drug effects , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/isolation & purification , Microbial Sensitivity Tests , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Alanine/chemistry , Alanine/pharmacology , Alanine/analogs & derivatives , Drug Screening Assays, Antitumor , Peptides/chemistry , Peptides/pharmacology , Peptides/isolation & purification , Cell Line, Tumor , PyridazinesABSTRACT
Entomopathogenic fungus Metarhizium majus contains the nine-gene PPZ cluster, with ppzA, encoding a peramine-producing nonribosomal peptide synthetase, as the central component. In this work, the roles of two α-ketoglutarate, iron-dependent oxygenases encoded by the PPZ genes ppzC and ppzD were elucidated. PpzD was found to produce both trans-4-hydroxy-l-proline and trans-3-hydroxy-l-proline in a 13.1:1 ratio, yielding a key precursor for peramine biosynthesis. PpzC was found to act directly on peramine, yielding the novel analogue 8-hydroxyperamine.
