Lugdunin is an investigational

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...

, classified as a

thiazolidine Thiazolidine is a heterocyclic organic compound with the formula (CH2)3(NH)S. It is a 5-membered saturated ring with a thioether group and an amine group in the 1 and 3 positions. It is a sulfur analog of oxazolidine. Thiazolidine is a colorless ...

-containing

cyclic peptide Cyclic peptides are polypeptide chains which contain a circular sequence of bonds. This can be through a connection between the amino and carboxyl ends of the peptide, for example in cyclosporin; a connection between the amino end and a side chai ...

. It was isolated in 2016 after ''

Staphylococcus lugdunensis ''Staphylococcus lugdunensis'' is a coagulase-negative member of the genus ''Staphylococcus'', consisting of Gram-positive bacteria with spherical cells that appear in clusters. History It was first described in 1988 after being differentiate ...

'' was identified as the species of bacteria from the

human nose The human nose is the most protruding part of the face. It bears the nostrils and is the first organ of the respiratory system. It is also the principal organ in the olfactory system. The shape of the nose is determined by the nasal bones ...

that suppressed growth of species of disease-causing bacteria in that part of the human microbiome. Lugdunin is a non-ribosomally synthesized cyclic peptide that inhibits growth of ''

Staphylococcus aureus ''Staphylococcus aureus'' is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often positive ...

'' 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''. Lugdunin NRPS

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. 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 Adenylylation, more commonly known as AMPylation, is a process in which an adenosine monophosphate (AMP) molecule is covalently attached to the amino acid side chain of a protein. This covalent addition of AMP to a hydroxyl side chain of the prote ...

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.

References

External links

* Antimicrobial peptides Cyclic peptides {{antibiotic-stub