The cyclothiazomycins are a group of

natural products 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 sy ...

, classified as thiopeptides, which are produced by various ''

Streptomyces ''Streptomyces'' is the largest genus of Actinomycetota and the type genus of the family Streptomycetaceae. Over 500 species of ''Streptomyces'' bacteria have been described. As with the other Actinomycetota, streptomycetes are gram-positive, ...

'' species of bacteria. These compounds are

ribosomally synthesized and post-translationally modified peptides Ribosomally synthesized and post-translationally modified peptides (RiPPs), also known as ribosomal natural products, are a diverse class of natural products of ribosomal origin. Consisting of more than 20 sub-classes, RiPPs are produced by a var ...

(RiPPs) and can be further classified as thiopeptides. The overall structure of the cyclothiazomycins comprises a

macrocyclic Macrocycles are often described as molecules and ions containing a ring of twelve or more atoms. Classical examples include the crown ethers, calixarenes, porphyrins, and cyclodextrins. Macrocycles describe a large, mature area of chemistry. ...

bicyclic In chemistry, a bicyclic molecule () is a molecule that features two joined rings. Bicyclic structures occur widely, for example in many biologically important molecules like α-thujene and camphor. A bicyclic compound can be carbocyclic (a ...

peptide containing several

thiazole Thiazole, or 1,3-thiazole, is a heterocyclic compound that contains both sulfur and nitrogen. The term 'thiazole' also refers to a large family of derivatives. Thiazole itself is a pale yellow liquid with a pyridine-like odor and the molecular fo ...

s and

thiazoline Thiazolines (or dihydrothiazoles) are a group of isomeric 5-membered heterocyclic compounds containing both sulfur and nitrogen in the ring. Although unsubstituted thiazolines are rarely encountered themselves, their derivatives are more common ...

s. The cyclothiazomycins are reported to have multiple inhibitory effects ranging from decreasing blood pressure to interfering with RNA transcription; they also exhibit some

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

activity.

History

Cylothiazomycin A was first isolated from ''Streptomyces'' sp. NR0516 in 1991. The structure of cyclothiazomycin A was solved via

NMR spectroscopy Nuclear magnetic resonance spectroscopy, most commonly known as NMR spectroscopy or magnetic resonance spectroscopy (MRS), is a spectroscopic technique to observe local magnetic fields around atomic nuclei. The sample is placed in a magnetic fiel ...

and chemical degradation. Previously, a peptide compound 5102-II had been isolated in 1982 from ''

Streptomyces hygroscopicus ''Streptomyces hygroscopicus'' is a bacterial species in the genus ''Streptomyces''. It was first described by Hans Laurits Jensen in 1931. Biochemistry Cultures of different strains of ''S. hygroscopicus'' can be used to produce a number of ...

'' 10-22. The discovery of the

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

s responsible for the biosynthesis of cyclothiazomycin in 2010 showed that 5102-II and cyclothiazomycin A were the same compound.

Structural analog A structural analog (analogue in modern traditional English; Commonwealth English), also known as a chemical analog or simply an analog, is a compound having a structure similar to that of another compound, but differing from it in respect to a ...

ues cyclothiazomycin B1 and B2 were isolated from ''Streptomyces'' sp. A307 and solved in 2006 with the help of high-resolution

mass spectrometry Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a '' mass spectrum'', a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is u ...

and NMR spectroscopy. A third analogue, cyclothiazomycin C, was discovered in 2014 with the aid of

genome mining Genome mining describes the exploitation of genomic information for the discovery of biosynthetic pathways of natural products and their possible interactions. It depends on computational technology and bioinformatics tools. The mining process reli ...

, nucleophilic 1,4-addition labeling reactions, high resolution mass spectrometry, and NMR spectroscopy.

Structure

The cyclothiazomycins are thiazole-containing

and macrocyclic peptides that are structurally similar to

thiostrepton Thiostrepton is a natural cyclic oligopeptide antibiotic of the thiopeptide class, derived from several strains of streptomycetes, such as '' Streptomyces azureus'' and '' Streptomyces laurentii''. Thiostrepton is a natural product of the ribo ...

and noshiheptide. Formally classified as thiopeptides within the larger family of ribosomally synthesized and post-translationally modified peptides (RiPPs), the cyclothiazomycins are initially biosynthesized as peptides which subsequently undergo chemical modifications, including

macrocyclization Macrocycles are often described as molecules and ions containing a ring of twelve or more atoms. Classical examples include the crown ethers, calixarenes, porphyrins, and cyclodextrins. Macrocycles describe a large, mature area of chemistry. ...

aromatization Aromatization is a chemical reaction in which an aromatic system is formed from a single nonaromatic precursor. Typically aromatization is achieved by dehydrogenation of existing cyclic compounds, illustrated by the conversion of cyclohexane into ...

, cyclodehydration, and

dehydrogenation In chemistry, dehydrogenation is a chemical reaction that involves the removal of hydrogen, usually from an organic molecule. It is the reverse of hydrogenation. Dehydrogenation is important, both as a useful reaction and a serious problem. A ...

. Cyclothiazomycins exist as three analogues that differ at two

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...

residues in the core peptide. The image below denotes in red the differences between the analogues as well as the amino acid sequence that becomes the final compounds. The structure of cyclothiazomycin A was established primarily by

two-dimensional nuclear magnetic resonance spectroscopy Two-dimensional nuclear magnetic resonance spectroscopy (2D NMR) is a set of nuclear magnetic resonance spectroscopy (NMR) methods which give data plotted in a space defined by two frequency axes rather than one. Types of 2D NMR include correlation ...

. Cyclothiazomycin A contains a

dehydroalanine Dehydroalanine (Cα,β-didehydroalanine, α,β-di-dehydroalanine, 2-aminoacrylate, or 2,3-didehydroalanine) is a dehydroamino acid. It does not exist in its free form, but it occurs naturally as a residue found in peptides of microbial origin. As ...

and two dehydrohomoalanine residues within a bicyclic, macrocyclic scaffold composed of thiazolines, thiazoles, and a trisubstituted

pyridine Pyridine is a basic (chemistry), basic heterocyclic compound, heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom. It is a highly flammable, weakl ...

. Cyclothiazomycin B and C vary from cyclothiazomycin A at the second and third

threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COO ...

residues in the core sequence of the precursor peptide. In cyclothiazomycin B, the second threonine is an

arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the a ...

. Cyclothiazomycin B exists as a pair of

diastereomer In stereochemistry, diastereomers (sometimes called diastereoisomers) are a type of stereoisomer. Diastereomers are defined as non-mirror image, non-identical stereoisomers. Hence, they occur when two or more stereoisomers of a compound have dif ...

s, cyclothiazomycin B1 and cyclothiazomycin B2, that differ at the configuration of one of its dehydrohomoalanine moieties. Cyclothiazomycin B1 and B2 interconvert by isomerization in solution but are stable in the solid state. Cyclothiazomycin C has a

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated &minu ...

in place of the second threonine residue found in cyclothiazomycin A and a

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − for ...

residue in place of the third threonine residue, resulting in a dehydroalanine instead of the dehydrohomoalanine observed in cyclothiazomycin A. Cyclothiazomycin-family

Biosynthesis

Cyclothiazomycin is part of a class of natural products that are ribosomally synthesized and post-translationally modified peptides (RiPPs). As such, cyclothiazomycin begins as a peptide that is synthesized in the bacterial ribosome. A series of chemical steps by biosynthetic enzymes transform the original peptide into the final (mature) natural product. The gene encoding for cyclothiazomycin begins with a short

open reading frame In molecular biology, open reading frames (ORFs) are defined as spans of DNA sequence between the start and stop codons. Usually, this is considered within a studied region of a Prokaryote, prokaryotic DNA sequence, where only one of the #Six-fra ...

(ORF) ''ctmA'' (''cltA''). ''CtmD'' (''cltB'') encodes a "fused" TOMM cyclodehydratase believed to take part in the formation of thiazolines. The enzyme encoded by the ''ctmB'' (''cltC'') gene is believed to catalyze the dehydrogenation of thiazolines to thiazoles. ''CtmE'' and ''ctmF'' (''ctlE'' and ''cltF'') each encode a split lanthipeptide dehydratase which dehydrates

and

and dehydrobutyrine. ''CtmG'' (''cltG'') is believed to aide in the production of the central pyridine. ''CtmI'' (''cltD'') encodes a ThiF-like protein. ''CtmH'' (''cltH'') is a LuxR-type regulatory gene. ''CtmJK'' are not present in the cycloythiazomycin A and C clusters; there is no known function. The ''cltN'' gene is believed to encode an enzyme that is involved in the formation of the tertiary thioether, however this has not been proven and ''cltN'' is not regulated by ''ctmH''.''CtmA'', ''ctmD'', ''ctmF'', and ''ctmG'' deletion leads to the disappearance of cyclothiazomycin A. ''CtmH'' is a LuxR-type regulatory gene that was shown to regulate ''ctmA''-''ctmL''.

Bioactivity

Each analogue of cyclothiazomycin is believed to interact with at least one biological target. Cyclothiazomycin A has been shown to inhibit blood plasma renin leading to a decrease blood pressure; it also exhibits weak anti-fungal activity. Cyclothiazomycin B shows inhibitory activity against

RNA polymerase In molecular biology, RNA polymerase (abbreviated RNAP or RNApol), or more specifically DNA-directed/dependent RNA polymerase (DdRP), is an enzyme that synthesizes RNA from a DNA template. Using the enzyme helicase, RNAP locally opens the ...

, and it is believed to act by reducing ribosome dependent

GTPase GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a ...

. Cyclothiazomycin B also exhibits anti-fungal activity by binding to the

chitin Chitin ( C8 H13 O5 N)n ( ) is a long-chain polymer of ''N''-acetylglucosamine, an amide derivative of glucose. Chitin is probably the second most abundant polysaccharide in nature (behind only cellulose); an estimated 1 billion tons of chit ...

cell wall A cell wall is a structural layer surrounding some types of cells, just outside the cell membrane. It can be tough, flexible, and sometimes rigid. It provides the cell with both structural support and protection, and also acts as a filtering mec ...

s, thus producing a fragile cell wall. Recently discovered cyclothiazomycin C has an unknown biological role, but cyclothiazomycins B and C both exhibit

antibacterial 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 ...

activity against

Gram-positive bacteria In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. Gram-positive bact ...

, including ''

Bacillus anthracis ''Bacillus anthracis'' is a gram-positive and rod-shaped bacterium that causes anthrax, a deadly disease to livestock and, occasionally, to humans. It is the only permanent (obligate) pathogen within the genus '' Bacillus''. Its infection is ...

''.

References

{{reflist Thiopeptides