Lugdunin is a non-ribosomally synthesized cyclic peptide that inhibits growth of Staphylococcus aureus strains.[5][6][7] The lugdunin genes are located on a 30-kbp operon. The genes lugA, lugB, lugC, and lugD encode four non-ribosomal peptide synthases, which are preceded by a putative regulator gene lugR.[8]
The NRPS synthesis of lugdunin prior to cyclization and thiazolidine formation.
Biosynthesis
Lugdunin is synthesized by non ribosomal peptide synthetases in S. lugdunensis. The molecule is a cyclic peptide composed of a thiazolidine heterocycle and three D amino acids. The operon responsible for lugdunin synthesis is approximately 30 kb and contains four non ribosomal peptide synthetase genes. The operon contains a phosphopantetheinyl transferase, monooxygenase, an unknown tailoring enzyme, a regulator gene, and a type II thioesterase.[9] Phosphopantetheinyl transferases carry out the activation of T domains, which act as carrier proteins. Monooxygenases incorporate a single hydroxyl into a lugdunin intermediate. The type II thioesterase is utilized to remove intermediates that stall during biosynthesis.[citation needed]
A surprising note about lugdunin is that the operon only encodes five adenylation domains, an interestingly small amount for such a large molecule. This discrepancy is accounted for by the addition of three consecutive valine residues in alternating D and L configurations by LugC. The thiazolidine ring forms following the release of the metabolite via reduction. The N-terminal L-Cysteine residue nucleophilically attacks the carbonyl[citation needed] on the C-terminal L-valine residue, thus forming an imine macrocycle. The Schiff base formed in this reaction is then nucleophilically attacked by a cysteine thiol which produces the thiazolidine heterocycle previously described.[citation needed]
^Bitschar K, Sauer B, Focken J, Dehmer H, Moos S, Konnerth M, Schilling NA, Grond S, Kalbacher H, Kurschus FC, Götz F, Krismer B, Peschel A, Schittek B. Lugdunin amplifies innate immune responses in the skin in synergy with host- and microbiota-derived factors. Nat Commun. 2019 Jun 21;10(1):2730. doi:10.1038/s41467-019-10646-7PMID31227691
^Krauss S, Zipperer A, Wirtz S, Saur J, Konnerth MC, Heilbronner S, Torres Salazar BO, Grond S, Krismer B, Peschel A. Secretion of and Self-Resistance to the Novel Fibupeptide Antimicrobial Lugdunin by Distinct ABC Transporters in Staphylococcus lugdunensis. Antimicrob Agents Chemother. 2020 Dec 16;65(1):e01734-20. doi:10.1128/AAC.01734-20PMID33106269
^Berscheid A, Straetener J, Schilling NA, Ruppelt D, Konnerth MC, Schittek B, Krismer B, Peschel A, Steinem C, Grond S, Brötz-Oesterhelt H. The microbiome-derived antibacterial lugdunin acts as a cation ionophore in synergy with host peptides. mBio. 2024 Sep 11;15(9):e0057824. doi:10.1128/mbio.00578-24PMID39133006
^Krismer, Bernhard; Peschel, Andreas; Grond, Stephanie; Brötz-Oesterhelt, Heike; Schittek, Birgit; Kalbacher, Hubert; Willmann, Matthias; Marschal, Matthias; Slavetinsky, Christoph; Schilling, Nadine A.; Burian, Marc; Weidenmaier, Christopher; Janek, Daniela; Berscheid, Anne; Laux, Claudia; Konnerth, Martin C.; Zipperer, Alexander (July 2016). "Extended Data Figure 1: Gene cluster of lugdunin and generation of S. lugdunensis IVK28-Xyl". Nature. 535 (7613): 511–516. Bibcode:2016Natur.535..511Z. doi:10.1038/nature18634. PMID27466123. S2CID205249755.
