Landornamides: Antiviral Ornithine‐Containing Ribosomal Peptides Discovered through Genome Mining

Abstract

Proteusins are a family of bacterial ribosomal peptides that largely remain hypothetical genome‐predicted metabolites. The only known members are the polytheonamide‐type cytotoxins, which have complex structures due to numerous unusual posttranslational modifications (PTMs). Cyanobacteria contain large numbers of putative proteusin loci. To investigate their chemical and pharmacological potential beyond polytheonamide‐type compounds, we characterized landornamide A, the product of the silent osp gene cluster from Kamptonema sp. PCC 6506. Pathway reconstruction in E. coli revealed a peptide combining lanthionines, d‐residues, and, unusually, two ornithines introduced by the arginase‐like enzyme OspR. Landornamide A inhibited lymphocytic choriomeningitis virus infection in mouse cells, thus making it one of the few known anti‐arenaviral compounds. These data support proteusins as a rich resource of chemical scaffolds, new maturation enzymes, and bioactivities.

Combinatorial biosynthesis for the generation of new-to-nature peptide antimicrobials

“…In addition, with the knowledge of the NRPS and RiPP machineries combined, we envision the merging of these two natural peptide product worlds, either by creating non-ribosomal antimicrobial peptide structures with a RiPP machinery, or combining RiPP tailoring enzymes with NRPS megasynthetases [90,116]. The potential of the former approach has recently been explored by the functional mimicking of the NRP brevicidine with a RiPP machinery [117,118].…”

“…The potential of the former approach has recently been explored by the functional mimicking of the NRP brevicidine with a RiPP machinery [117,118]. Moreover, the possibility of introducing D-amino acids, methylation, glycosylation, several side chain cross-links, non-canonical amino acids as well as fatty acids on antimicrobial peptide scaffolds will further expand this approach, given SAR studies of a carefully chosen antimicrobial NRP scaffold as well as detailed knowledge on leader requirements and promiscuity of the RiPP machinery are known [90,113,[118][119][120][121][122]. Interestingly, also the first examples of natural hybrid biosynthetic clusters involving both NRPS and RiPPs elements have been described [119,123,124].…”

“…In addition to the vast amount of knowledge on the structure-activity relationships of several antimicrobial RiPPs and their biosynthetic enzymes generated from these core peptide mutagenesis studies, the combinatorial possibility of RiPP enzymes has been explored, where enzymes from different biosynthetic gene clusters are combined to act on a single substrate to generate natural product analogues (Figure 2C). The possibility of this approach has been inspired by the discovery of several natural 'hybrid' RiPP biosynthesis pathways [62,89,90].…”

Beyond Soil-Dwelling Actinobacteria: Fantastic Antibiotics and Where to Find Them

“…The first representative of this family was polytheonamide, from an uncultivated sponge symbiont (see above), but a genomic survey of cyanobacterial genomes revealed the presence of over 50 proteusin-like BGCs in cyanobacteria, many of them with multiple precursor peptides. Expression of one of these clusters in E. coli resulted into the production of landornamides ( Figure 12 ), the first characterized cyanobaterial proteusin [ 293 ]. Similarly, the spliceotide family was identified in cyanobacteria after genomic studies revealed the presence of clusters containing nif11 domain-containing precursor peptides, associated with orphan radical SAM enzymes.…”