Pleuromutilin and its derivatives are antibacterial drugs that inhibit

protein synthesis Protein biosynthesis, or protein synthesis, is a core biological process, occurring inside cells, balancing the loss of cellular proteins (via degradation or export) through the production of new proteins. Proteins perform a number of critica ...

in bacteria by binding to the

peptidyl transferase The peptidyl transferase center (, PTC) is an Aminoacyltransferases, aminoacyltransferase ribozyme (RNA enzyme) located in the large subunit of the ribosome. It forms peptide bonds between adjacent amino acids during the Translation (genetics), ...

component of the

50S 50 S is the larger subunit of the 70S ribosome of prokaryotes, i.e. bacteria and archaea. It is the site of inhibition for antibiotics such as macrolides, chloramphenicol, clindamycin, and the pleuromutilins. It includes the 5S ribosom ...

subunit of

ribosome Ribosomes () are molecular machine, macromolecular machines, found within all cell (biology), cells, that perform Translation (biology), biological protein synthesis (messenger RNA translation). Ribosomes link amino acids together in the order s ...

s. This class of antibiotics includes the licensed drugs lefamulin (for systemic use in humans), retapamulin (approved for

topical A topical medication is a medication that is applied to a particular place on or in the body. Most often topical medication means application to body surfaces such as the skin or mucous membranes to treat ailments via a large range of classes ...

use in humans),

valnemulin Valnemulin, sold under the brand name Econor among others, is a pleuromutilin antibiotic used to treat swine dysentery, ileitis, colitis, and pneumonia. It is also used for the prevention of intestinal infections of swine. Valnemulin has been o ...

and

tiamulin Tiamulin (previously thiamutilin) is a pleuromutilin antibiotic drug that is used in veterinary medicine particularly for pigs and poultry. Tiamulin is a diterpene Diterpenes are a class of terpenes composed of four isoprene units, often with ...

(approved for use in animals) and the

investigational drug The United States Food and Drug Administration's Investigational New Drug (IND) program is the means by which a pharmaceutical company obtains permission to start human clinical trials and to ship an experimental drug across state lines (usually ...

azamulin.

History

Pleuromutilin was discovered as an antibiotic in 1951. It is derived from the

fungi A fungus (: fungi , , , or ; or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and mold (fungus), molds, as well as the more familiar mushrooms. These organisms are classified as one ...

Omphalina mutila ''Omphalina'' is a genus of small agarics with white, nonamyloid, basidiospores and decurrent gills. Typically the cap has a deep central depression giving the umbrella-like to funnel-shaped cap the appearance of a belly button, or a belly with a ...

'' (formerly ''Pleurotus mutilus'') and '' Clitopilus passeckerianus'' (formerly ''Pleurotus passeckerianus''), and has also been found in '' Drosophila subatrata'', ''

Clitopilus scyphoides ''Clitopilus'' is a genus of fungi in the family Entolomataceae. The genus has a widespread distribution, especially in northern temperate areas. Although a 2008 estimate suggested about 30 species in the genus, a more recent publication (2009) u ...

'', and some other ''

Clitopilus ''Clitopilus'' is a genus of fungi in the family Entolomataceae. The genus has a widespread distribution, especially in northern temperate areas. Although a 2008 estimate suggested about 30 species in the genus, a more recent publication (2009) u ...

'' species.

Total synthesis

The

total synthesis Total synthesis, a specialized area within organic chemistry, focuses on constructing complex organic compounds, especially those found in nature, using laboratory methods. It often involves synthesizing natural products from basic, commercially ...

of pleuromutilin has been reported.

Biosynthesis

Pleuromutilin belongs to the class of secondary metabolites known as

terpene Terpenes () are a class of natural products consisting of compounds with the formula (C5H8)n for n ≥ 2. Terpenes are major biosynthetic building blocks. Comprising more than 30,000 compounds, these unsaturated hydrocarbons are produced predomi ...

s, which are produced in fungi through the

mevalonate pathway The mevalonate pathway, also known as the isoprenoid pathway or HMG-CoA reductase pathway is an essential metabolic pathway present in eukaryotes, archaea, and some bacteria. The pathway produces two five-carbon building blocks called isopentenyl ...

(MEP pathway). Its synthetic bottleneck lays on the production of the precursor

GGPP Geranylgeranyl pyrophosphate is an intermediate in the biosynthesis of diterpenes and diterpenoids. It is also the precursor to carotenoids, gibberellins, tocopherols, and chlorophylls. It is also a precursor to geranylgeranylated proteins, whic ...

and the following formation of the tricyclic structure, which is catalyzed by ''Pl-cyc'', a bifunctional diterpene synthase (DTS). This Cyclase shows a new class II DTS activity, catalyzes a ring contraction and the formation of a 5-6-bicyclic ring structure. Specifically, DTS shows two catalytic distinguishable domains: On the one hand it has at the N-terminal region a class II DTS domain, which catalyzes a cascade cyclization, resulting in a

decalin Decalin (decahydronaphthalene, also known as bicyclo .4.0ecane and sometimes decaline), a bicyclic organic compound, is an industrial solvent. A colorless liquid with an aromatic odor, it is used as a solvent for many resins or fuel additives. I ...

core. Subsequently, variable 1,2-proton and methyl shifts occur to translocate the

carbocation Carbocation is a general term for ions with a positively charged carbon atom. In the present-day definition given by the IUPAC, a carbocation is any even-electron cation with significant partial positive charge on a carbon atom. They are further ...

towards one of the two interconnecting C-atoms and this intermediate induces a base-catalyzed ring contraction. Therefore, class II DTS promotes in general a ring contraction during the cyclisation of

. On the other hand, at the C-terminal end it has a class I DTS domain, which catalyzes a conjugated dephosphorylation, generating the 8-membered cyclic core, followed by a 1,5-proton shift and a stereospecific hydroxylation to obtain premutilin. Pleuromutilin proposed cyclisation mechanism

Pleuromutilin proposed cyclisation mechanism

Additionally, three

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

s (''Pl-p450-1, Pl-p450-2 and Pl-p450-3'') are involved in the final steps of the pleuromutilin biosynthetic pathway. The P450-1 and P450-2 are essential for hydroxylation of two ring structures regarding the premutilin skeleton, oxidating specifically at position C-11 and C-3, respectively. The short-chain dehydrogenase/reductase enzyme (''Pl-sdr'') has a regiospecific activity and converts the 3-hydroxy group to a ketone, forming the intermediate

mutilin Retapamulin is a topical antibiotic developed by GlaxoSmithKline. It is the first drug in the new class of pleuromutilin antibiotics to be approved for human use. It is marketed as an ointment under the brand names Altabax and Altargo. Retapamul ...

. Acetyltransferase (''Pl-at''f) catalyzes the transfer of acetyl group to 14-OH of mutilin. Finally, ''Pl-p450-3'' hydroxylates the α-methyl group of the acetyl side chain generating pleuromutilin.

History

Total synthesis

Biosynthesis

References

Further reading