Discovery and Biosynthetic Investigation of a New Antibacterial Dehydrated Non‐Ribosomal Tripeptide

Abstract

Dehydroalanine (Dha) and dehydrobutyrine (Dhb) display considerable flexibility in a variety of chemical and biological reactions. Natural products containing Dha and/or Dhb residues are often found to display diverse biological activities. While the (Z) geometry is predominant in nature, only a handful of metabolites containing (E)‐Dhb have been found thus far. Here we report discovery of a new antimicrobial peptide, albopeptide, through NMR analysis and chemical synthesis, which contains two contiguous unsaturated residues, Dha‐(E)‐Dhb. It displays narrow‐spectrum activity against vancomycin‐resistant Enterococcus faecium. In‐vitro biochemical assays show that albopeptide originates from a noncanonical NRPS pathway featuring dehydration processes and catalysed by unusual condensation domains. Finally, we provide evidence of the occurrence of a previously untapped group of short unsaturated peptides in the bacterial kingdom, suggesting an important biological function in bacteria.

The structure and biosynthesis of heinamides A1–A3 and B1–B5, antifungal members of the laxaphycin lipopeptide family

“…Thr dehydration to Dhb by the condensation domain of the modified AA clade has been shown experimentally in the biosynthesis of albopeptide. 73 The condensation domain LxaC1 3 following the Thr incorporation module was found to belong this clade, as shown in phylogenetic studies 10,74 (Fig. S13 †).…”

Antimicrobial peptides: mechanism of action, activity and clinical potential

“…One group is the peptides synthesized by ribosomes with relatively narrow antibacterial activity against bacteria and fungi, and the other group is the peptides synthesized by non-ribosomes with broad antibacterial activity [ 175 ]. Wang et al [ 176 ] discovered a new short non-ribosomal AMP, albopeptide 6, in the culture broth of Streptomyces albofaciens , which displayed a narrow-spectrum activity against vancomycin-resistant Enterococcus faecium . Nisin is a member of the bacteriocins family and has high antibacterial activity against a wide range of Gram-positive bacteria and even Gram-negative bacteria [ 177 ].…”

New Scabimycins A-C Isolated from Streptomyces acidiscabies (Lu19992)

“…This amino acid arises from dehydration of threonine, which occurs either through action of a dehydratase enzyme or via the elimination of phosphorylated residues [ 27 ]. Dhbs are often found in ribosomally synthesized and post-translationally modified peptides (RiPPs), e.g., in thiopeptides such as cyclothiazomycin [ 28 ] or in depsipeptides such as tumescenamides [ 29 ], but also in peptides synthesized by NRPS, e.g., in albopeptin or in the recently discovered malpinins [ 30 , 31 ]. The genome of S. acidiscabies harbors several NRPS and RiPPs biosynthetic gene clusters, which became apparent after genome analysis using the antiSMASH online tool [ 32 ].…”

“…To certainly exclude antibacterial activity of these compounds, a wider range of pathogenic bacteria needs to be tested. For example the recently discovered tripeptide albopeptin, which contain also the amino acid dhb, was found to be active against the clinical isolate of vancomycin-resistant Enterococcus faecium K60–39 [ 30 ].…”