Thiostrepton is a natural cyclic

oligopeptide An oligopeptide, often just called peptide ('' oligo-'', "a few"), consists of two to twenty amino acids and can include dipeptides, tripeptides, tetrapeptides, and pentapeptides. Some of the major classes of naturally occurring oligopeptides incl ...

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 ...

of the

thiopeptide Thiopeptides (thiazolyl peptides) are a class of peptide antibiotics produced by bacteria. They have antibiotic activity against Gram-positive bacteria, but little or no activity against Gram-negative bacteria. Many of the members of this class s ...

class, derived from several strains of streptomycetes, such as '' Streptomyces azureus'' and '' Streptomyces laurentii''. Thiostrepton is a

natural product A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical syn ...

of the ribosomally synthesized and post-translationally modified peptide (RiPP) class.

History

Thiostrepton was discovered by Donovick ''et al.'' who described its antibacterial properties in 1955.

Dorothy Crowfoot Hodgkin Dorothy Mary Crowfoot Hodgkin (née Crowfoot; 12 May 1910 – 29 July 1994) was a Nobel Prize-winning British chemist who advanced the technique of X-ray crystallography to determine the structure of biomolecules, which became essential fo ...

solved the structure of thiostrepton in 1970. Early in 1978, Bycroft and Gowland proposed the biosynthesis of thiostrepton, which was still unclear until 2009. Several studies of thiopeptide biosynthesis have been contemporarily published in 2009 and two of them (Liao ''et al.'' and Kelly ''et al.'') included the similar biosynthesis of thiostrepton: it's ribosomally synthesized from thiostrepton biosynthetic genes (tsr genes) and posttranslational modification is needed. A total synthesis of thiostrepton was completed by

K.C. Nicolaou Kyriacos Costa Nicolaou ( el, Κυριάκος Κ. Νικολάου; born July 5, 1946) is a Cypriot-American chemist known for his research in the area of natural products total synthesis. He is currently Harry C. and Olga K. Wiess Professor o ...

, ''et al.'' in 2004.

Applications

Thiostrepton has been used in veterinary medicine in

mastitis Mastitis is inflammation of the breast or udder, usually associated with breastfeeding. Symptoms typically include local pain and redness. There is often an associated fever and general soreness. Onset is typically fairly rapid and usually occurs ...

caused by

gram-negative Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall ...

organisms and in dermatologic disorders. It is mostly used in complex ointments containing

neomycin Neomycin is an aminoglycoside antibiotic that displays bactericidal activity against gram-negative aerobic bacilli and some anaerobic bacilli where resistance has not yet arisen. It is generally not effective against gram-positive bacilli and ...

nystatin Nystatin, sold under the brandname Mycostatin among others, is an antifungal medication. It is used to treat '' Candida'' infections of the skin including diaper rash, thrush, esophageal candidiasis, and vaginal yeast infections. It may also be ...

, Thiostrepton and topical

steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...

s. It is also active against gram-positive bacteria. It is notable that ointments for human usage contain

, and topical

s, but no thiostrepton. Thiostrepton was reported (in 2008) to exhibit activity against breast cancer cells through targeting the transcription factor forkhead box M1 (

FOXM1 Forkhead box protein M1 is a protein that in humans is encoded by the ''FOXM1'' gene. The protein encoded by this gene is a member of the FOX family of transcription factors. Its potential as a target for future cancer treatments led to it being ...

), also in 2011. It has also been shown to circumvent acquired cisplatin resistance in breast cancer cells under in invitro conditions. Thiostrepton is used in molecular biology as a reagent for both positive and negative selection of genes involved in nucleotide metabolism.

Biosynthesis

There are total 21 genes (tsrA~tsrU) in the biosynthetic gene cluster. The precursor of thiostrepton contains 58 amino acids in the peptide chain, which includes 41-aa leader peptide (LP) and 17-aa structural peptide (IASASCTTCICTCSCSS). Once the precursor is synthesized, cyclodehydratase tsrO and dehydrogenase tsrM catalyze the formation of thiazole or thiazoline from every cysteine residues in the peptide chain. After thiazole/thiazoline formation, dehydratases tsrJ, K and S then convert all the serine residues into dehydroalanines. A hetero Diels-Alder cyclization of the central dehydropiperidine (at S5, C13, and S14) has been suggested by Bycroft back to 1978 and been employed in the chemical synthesis of this core structure by Nicolaou ''et al.'' in 2005. An alternative mechanism of the dehydropiperidine formation has also been suggested by Kelly ''et al''. in 2009. Nevertheless, based on experimental evidence, tsrN and L are suggested to be responsible for the hetero Diels-Alder cyclization. The quinaldic acid moiety is suggested to be synthesized by the nine genes tsrFAEBDUPQI from tryptophan and then results in the closure of quinaldic acid macrocycle. At last, tsrR serves as a candidate for the oxidation of the Ile residue to afford thiostrepton. Biosynthesis of Thiostrepton

Alternative mechanism for the formation of the dehydropiperidine core

Alternative Mechanism for the dehydropiperidine thiopeptides biosynthesis

Total synthesis

In 2005, Nicolaou ''et al.'' published the total synthesis of thiostrepton. At first, they constructed the key building blocks of thiostrepton (1): dehydropiperidine core (2), thiazoline macrocycle (3), bis-dehydroalanine tail (4), and quinaldic acid macrocycle (5). Then they assembled the building blocks sequentially as shown in the synthetic scheme (compound numbers are from the reference).

Building blocks

Synthetic scheme

References

{{reflist, 33em Thiopeptides Heterocyclic compounds with 7 or more rings Antibiotics