The anti-staphylococcal lipolanthines are ribosomally synthesized lipopeptides.

The potent antibacterial lanthipeptide microvionin, isolated from a culture of Microbacterium arborescens, exhibits a new triamino-dicarboxylic acid moiety, termed avionin, and an unprecedented N-terminal guanidino fatty acid. We identified the corresponding biosynthetic gene cluster and reconstituted central steps of avionin biosynthesis in vitro. Genome mining and isolation of nocavionin from Nocardia terpenica revealed a widespread distribution of this lanthipeptide class, termed lipolanthines, which may be useful as future antimicrobial drugs.

A Convergent Total Synthesis of the Death Cap Toxin α-Amanitin.

The toxic bicyclic octapeptide α-amanitin is mostly found in different species of the mushroom genus Amanita, with the death cap (Amanita phalloides) as one of the most prominent members. Due to its high selective inhibition of RNA polymerase II, which is directly linked to its high toxicity, particularly to hepatocytes, α-amanitin received an increased attention as a toxin-component of antibody-drug conjugates (ADC) in cancer research. Furthermore, the isolation of α-amanitin from mushrooms as the sole source severely restricts compound supply as well as further investigations, as structure-activity relationship (SAR) studies. Based on a straightforward access to the non-proteinogenic amino acid dihydroxyisoleucine, we herein present a robust total synthesis of α-amanitin providing options for production at larger scale as well as future structural diversifications.

An Amphipathic Alpha-Helix Guides Maturation of the Ribosomally-Synthesized Lipolanthines.

The recently discovered strongly anti-Gram-positive lipolanthines represent a new group of lipidated, ribosomally synthesized and post-translationally modified peptides (RiPPs). They are bicyclic octapeptides with a central quaternary carbon atom (avionin), which is installed through the cooperative action of the class-III lanthipeptide synthetase MicKC and the cysteine decarboxylase MicD. Genome mining efforts indicate a widespread distribution and unprecedented biosynthetic diversity of lipolanthine gene clusters, combining elements of RiPPs, polyketide and non-ribosomal peptide biosynthesis. Utilizing NMR spectroscopy, we show that a (θxx)θxxθxxθ (θ=L, I, V, M or T) motif, which is conserved in the leader peptides of all class-III and -IV lanthipeptides, forms an amphipathic α-helix in MicA that destines the peptide substrate for enzymatic processing. Our results provide general rules of substrate recruitment and enzymatic regulation during lipolanthine maturation. These insights will facilitate future efforts to rationally design new lanthipeptide scaffolds with antibacterial potency.