Chemistry:Lugdunin
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][4]
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]
| 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 |
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 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|date=January 20
References
- ↑ Gallagher, James (2016-07-27). "Antibiotic resistance: 'Snot wars' study heralds new class of drugs". https://www.bbc.co.uk/news/health-36910766.
- ↑ Zipperer, Alexander; Konnerth, Martin C.; Laux, Claudia; Berscheid, Anne; Janek, Daniela; Weidenmaier, Christopher; Burian, Marc; Schilling, Nadine A. et al. (2016). "Human commensals producing a novel antibiotic impair pathogen colonization". Nature 535 (7613): 511–516. doi:10.1038/nature18634. PMID 27466123. Bibcode: 2016Natur.535..511Z.
- ↑ "Scientists find microbiotic treasure hidden in the nose". 2016-07-27. http://www.latimes.com/science/la-sci-sn-antibiotic-discovery-nose-20160727-snap-story.html.
- ↑ Durand, GA; Raoult, D; Dubourg, G (Apr 2019). "Antibiotic discovery: history, methods and perspectives". Int J Antimicrob Agents 53 (4): 371–382. doi:10.1016/j.ijantimicag.2018.11.010. PMID 30472287.
- ↑ Bitschar, K; Sauer, B; Focken, J; Dehmer, H; Moos, S; Konnerth, M; Schilling, NA; Grond, S et al. (Jun 2019). "Lugdunin amplifies innate immune responses in the skin in synergy with host- and microbiota-derived factors". Nat Commun 10 (1): 2730. doi:10.1038/s41467-019-10646-7. PMID 31227691.
- ↑ Krauss, S; Zipperer, A; Wirtz, S; Saur, J; Konnerth, MC; Heilbronner, S; Torres Salazar, BO; Grond, S et al. (Dec 2020). "Secretion of and Self-Resistance to the Novel Fibupeptide Antimicrobial Lugdunin by Distinct ABC Transporters in Staphylococcus lugdunensis". Antimicrob Agents Chemother 65 (1): e01734–20. doi:10.1128/AAC.01734-20. PMID 33106269.
- ↑ Berscheid, A; Straetener, J; Schilling, NA; Ruppelt, D; Konnerth, MC; Schittek, B; Krismer, B; Peschel, A et al. (Sep 2024). "The microbiome-derived antibacterial lugdunin acts as a cation ionophore in synergy with host peptides". mBio 15 (9): e0057824. doi:10.1128/mbio.00578-24. PMID 39133006.
- ↑ Krismer, Bernhard; Peschel, Andreas; Grond, Stephanie; Brötz-Oesterhelt, Heike; Schittek, Birgit; Kalbacher, Hubert; Willmann, Matthias; Marschal, Matthias et al. (July 2016). "Extended Data Figure 1: Gene cluster of lugdunin and generation of S. lugdunensis IVK28-Xyl". Nature 535 (7613): 511–516. doi:10.1038/nature18634. PMID 27466123. Bibcode: 2016Natur.535..511Z.
- ↑ Krauss, Sophia; Zipperer, Alexander; Wirtz, Sebastian; Saur, Julian; Konnerth, Martin C.; Heilbronner, Simon; Torres Salazar, Benjamin O.; Grond, Stephanie et al. (16 December 2020). "Secretion of and Self-Resistance to the Novel Fibupeptide Antimicrobial Lugdunin by Distinct ABC Transporters in Staphylococcus lugdunensis". Antimicrobial Agents and Chemotherapy 65 (1). doi:10.1128/AAC.01734-20. PMID 33106269.
External links
- "Press release: A potential lifesaver lies unrecognized in the human body". University of Tübingen. https://www.uni-tuebingen.de/uploads/media/16-07-27PM_Antibiotikum_Staphylokokken_en.pdf.
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