Lugdunin is an investigational antibiotic, classified as a thiazolidine-containing cyclic peptide. It was isolated in 2016 after Staphylococcus lugdunensis was identified as the species of bacteria from the human nose that suppressed growth of species of disease-causing bacteria in that part of the human microbiome.[1] [2] [3]
Lugdunin is a non-ribosomally synthesized cyclic peptide that inhibits growth of Staphylococcus aureus strains. 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.[4]
| Gene | locustag | protein size/aa | Genbank protein entry | RefSeq protein entry | |
|---|---|---|---|---|---|
| lugR | SLUG_RS03935 | 196 | CCB53263.1 | WP_002460032.1 | |
| lugA | SLUG_RS03940 | 2374 | CCB53264.1 | WP_002478842.1 | |
| SLUG_RS03945 | 124 | CCB53265.1 | WP_002460029.1 | ||
| lugB | SLUG_RS03950 | 1230 | CCB53266.1 | WP_014533237.1 | |
| lugC | SLUG_RS03955 | 2937 | CCB53267.1 | WP_002478844.1 | |
| lugT | SLUG_RS03960 | 228 | CCB53268.1 | WP_002460022.1 | |
| lugD | SLUG_RS03965 | 579 | CCB53269.1 | WP_002478846.1 |
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.[5] 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.
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[6] 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.