Talaropeptides A-D: Structure and Biosynthesis of Extensively N-methylated Linear Peptides From an Australian Marine Tunicate-Derived Talaromyces sp.

Abstract

An Australian marine tunicate-derived fungus, <i>Talaromyces</i> sp. CMB-TU011 was subjected to a program of analytical microbioreactor (MATRIX) cultivations, supported by UHPLC-QTOF profiling, to reveal conditions for producing a new class of extensively <i>N</i>-methylated 11-12 residue linear peptides, talaropeptides A-D (<b>2</b>-<b>5</b>). The structures for <b>2</b>-<b>5</b>, inclusive of absolute configurations, were determined by a combination of detailed spectroscopic and chemical (e.g., C₃ and C₁₈ Marfey's) analyses. We report on the biological properties of <b>2</b>-<b>5</b>, including plasma stability, as well as antibacterial, antifungal and cell cytotoxicity. The talaropeptide mega non-ribosomal peptide synthetase (NRPS) is described, as second only in size to that for the fungus-derived immunosuppressant cyclosporine (an 11-residue extensively <i>N</i>-methylated cyclic peptide).