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Lugdunin

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Lugdunin
Names
IUPAC name
(1R,4R,7S,10R,13S,16R,19S)-7-(1H-Indol-3-ylmethyl)-10-isobutyl-4,13,16,19-tetraisopropyl-21-thia-3,6,9,12,15,18,23-heptaazabicyclo[18.2.1]tricosane-2,5,8,11,14,17-hexone
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
  • InChI=1S/C40H62N8O6S/c1-19(2)15-27-35(50)45-31(21(5)6)38(53)47-32(22(7)8)39(54)48-33(23(9)10)40-44-29(18-55-40)36(51)46-30(20(3)4)37(52)43-28(34(49)42-27)16-24-17-41-26-14-12-11-13-25(24)26/h11-14,17,19-23,27-33,40-41,44H,15-16,18H2,1-10H3,(H,42,49)(H,43,52)(H,45,50)(H,46,51)(H,47,53)(H,48,54)/t27-,28+,29+,30-,31+,32-,33+,40?/m1/s1
    Key: QZNGYMKAHFFKCJ-ZBQZSICZSA-N
  • InChI=1/C40H62N8O6S/c1-19(2)15-27-35(50)45-31(21(5)6)38(53)47-32(22(7)8)39(54)48-33(23(9)10)40-44-29(18-55-40)36(51)46-30(20(3)4)37(52)43-28(34(49)42-27)16-24-17-41-26-14-12-11-13-25(24)26/h11-14,17,19-23,27-33,40-41,44H,15-16,18H2,1-10H3,(H,42,49)(H,43,52)(H,45,50)(H,46,51)(H,47,53)(H,48,54)/t27-,28+,29+,30-,31+,32-,33+,40?/m1/s1
    Key: QZNGYMKAHFFKCJ-ZBQZSICZBY
  • CC(C)C[C@@H]1C(=O)N[C@H](C(=O)N[C@@H](C(=O)N[C@H](C2N[C@@H](CS2)C(=O)N[C@@H](C(=O)N[C@H](C(=O)N1)Cc3c[nH]c4c3cccc4)C(C)C)C(C)C)C(C)C)C(C)C
Properties
C40H62N8O6S
Molar mass 783.05 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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
ChemDraw image depicting the synthesis of lugdunin. The synthesis proceeds in typical NRPS fashion with four distinct domains.
The NRPS synthesis of lugdunin prior to cyclization and thiazolidine formation.

Biosynthesis

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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]

References

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  1. ^ Gallagher, James (2016-07-27). "Antibiotic resistance: 'Snot wars' study heralds new class of drugs". BBC News. Retrieved 2016-07-27.
  2. ^ Zipperer, Alexander; Konnerth, Martin C.; Laux, Claudia; Berscheid, Anne; Janek, Daniela; Weidenmaier, Christopher; Burian, Marc; Schilling, Nadine A.; Slavetinsky, Christoph (2016). "Human commensals producing a novel antibiotic impair pathogen colonization". Nature. 535 (7613): 511–516. Bibcode:2016Natur.535..511Z. doi:10.1038/nature18634. PMID 27466123. S2CID 205249755.
  3. ^ "Scientists find microbiotic treasure hidden in the nose". Los Angeles Times. 2016-07-27. Retrieved 2016-07-27.
  4. ^ 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.
  5. ^ 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 (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. PMC 6588697. PMID 31227691.
  6. ^ Krauss, S; Zipperer, A; Wirtz, S; Saur, J; Konnerth, MC; Heilbronner, S; Torres Salazar, BO; Grond, S; Krismer, B; Peschel, A (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. PMC 7927808. PMID 33106269.
  7. ^ Berscheid, A; Straetener, J; Schilling, NA; Ruppelt, D; Konnerth, MC; Schittek, B; Krismer, B; Peschel, A; Steinem, C; Grond, S; Brötz-Oesterhelt, H (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. PMC 11389392. PMID 39133006.
  8. ^ 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. PMID 27466123. S2CID 205249755.
  9. ^ Krauss, Sophia; Zipperer, Alexander; Wirtz, Sebastian; Saur, Julian; Konnerth, Martin C.; Heilbronner, Simon; Torres Salazar, Benjamin O.; Grond, Stephanie; Krismer, Bernhard; Peschel, Andreas (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. PMC 7927808. PMID 33106269.
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