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

CAS Number

* 1989698-37-4

3D model (JSmol)

* Interactive image

ChEBI |

* CHEBI:133127 Y

ChemSpider |

* 57427231

PubChem CID

* 121596231

InChI

* 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

SMILES

* 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

Chemical formula

| 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).

Infobox references

Tracking categories (test):

* SizeSet

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

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.[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.[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[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.[citation needed]

## References

1. ↑ Gallagher, James (2016-07-27). "Antibiotic resistance: 'Snot wars' study heralds new class of drugs". https://www.bbc.co.uk/news/health-36910766.
2. ↑ 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.
3. ↑ "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.
4. ↑ 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.
5. ↑ Krauss, Sophia; Zipperer, Alexander; Wirtz, Sebastian; Saur, Julian; Konnerth, Martin C.; Heilbronner, Simon; Torres Salazar, Benjamin O.; Grond, Stephanie et al. (2020-12-16). "Secretion of and Self-Resistance to the Novel Fibupeptide Antimicrobial Lugdunin by Distinct ABC Transporters in Staphylococcus lugdunensis". Antimicrobial Agents and Chemotherapy 65 (1): e01734–20. doi:10.1128/AAC.01734-20. ISSN 0066-4804. PMID 33106269.
6. ↑ "Lugdunin - an overview | ScienceDirect Topics". https://www.sciencedirect.com/topics/chemistry/lugdunin.

## 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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*[CID]: Compound ID