Pleuromutilin and its derivatives are antibacterial drugs that inhibit

protein synthesis Protein biosynthesis (or protein synthesis) is a core biological process, occurring inside Cell (biology), cells, homeostasis, balancing the loss of cellular proteins (via Proteolysis, degradation or Protein targeting, export) through the product ...

in bacteria by binding to the

peptidyl transferase The peptidyl transferase is an aminoacyltransferase () as well as the primary enzymatic function of the ribosome, which forms peptide bonds between adjacent amino acids using tRNAs during the translation process of protein biosynthesis. The subst ...

component of the 50S subunit of

ribosome Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to ...

s. This class of antibiotics includes the licensed drugs

lefamulin Lefamulin, sold under the brand name Xenleta, is an antibiotic medication used it to treat adults with community-acquired bacterial pneumonia. It is taken by mouth or by injection into a vein. Relatively common side effects include diarrhea, ...

(for systemic use in humans),

retapamulin 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. Retapamu ...

(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 (trade name Econor or Biotilina) is a pleuromutilin antibiotic used to treat swine dysentery, ileitis, colitis and pneumonia. It is also used for the prevention of intestinal The gastrointestinal tract (GI tract, digestive tract, a ...

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 chemical compounds composed of four isoprene units, o ...

(approved for use in animals) and the investigational drug

azamulin Azamulin is a pleuromutilin antibiotic. , it is not marketed in the US or Europe. In pharmacological studies, the substance is used as an inhibitor of the liver enzymes CYP3A4 and CYP3A5 Cytochrome P450 3A5 is a protein that in humans is enc ...

History

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

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

'' Omphalina mutila'' (formerly ''Pleurotus mutilus'') and ''

Clitopilus passeckerianus ''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 ...

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

'' species.

Total synthesis

The

total synthesis Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. It usually refers to a process not involving the aid of biological processes, which distinguishes ...

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 > 1. Comprising more than 30,000 compounds, these unsaturated hydrocarbons are produced predominantly by plants, particularly conifers. Terpenes ar ...

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 A carbocation is an ion with a positively charged carbon atom. Among the simplest examples are the methenium , methanium and vinyl cations. Occasionally, carbocations that bear more than one positively charged carbon atom are also encountere ...

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 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...

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. Retapam ...

. 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