RETAPAMULIN Chemical Properties

Boiling point:

594.9±50.0 °C(Predicted)

Density 

1.16±0.1 g/cm3(Predicted)

storage temp. 

2-8°C

solubility 

insoluble in H2O; ≥114.8 mg/mL in EtOH; ≥16.15 mg/mL in DMSO

form 

solid

pka

14.65±0.70(Predicted)

color 

White to off-white

InChIKey

STZYTFJPGGDRJD-IFPFAXJDNA-N

CAS DataBase Reference

224452-66-8(CAS DataBase Reference)

RETAPAMULIN Usage And Synthesis

Description

Antibacterial retapamulin is a derivative of the natural product pleuromutilin and was developed by Glaxo and approved in the US in 2007 for the treatment of skin infections. It has a unique mechanism of action, inhibiting bacterial protein synthesis by inhibiting the larger subunit of the ribosome, and thus has no cross resistance to other antibacterial agents. Pleuromutilin is a tricyclic diterpenoid that was first isolated in 1951 from the edible mushroom Pleurotus mutilus. The first semisynthetic analogs tiamulin and valnemulin, developed for veterinary use, have been shown to interact uniquely with bacterial ribosomes by high affinity binding to a site on the 50S subunit. Binding to this site interferes with ribosomal peptidyl transferase activity, blocks P-site interactions, and prevents the evolution of active 50S ribosomal subunits. Retapamulin, the first pleuromutilin approved for human use, behaves similarly to selectively inhibit bacterial protein synthesis. This novel mechanism of action has been implicated in the lack of in vitro target-specific cross-resistance with other classes of antibiotics.

Originator

GlaxoSmithKline (US)

Uses

Retapamulin is a topical antibiotic, which binds to both E. coli and S. aureus ribosomes with similar potencies with Kd of 3 nM

Uses

Retapamulin is a semi-synthetic pleuormutilin prepared by reacting pleuromutilin tosylate with tropine-3-thiol to give a more hydrophobic analogue with a tertiary amine. This enables formulation as a stable hydrochloride salt. Retapamulin is a broad spectrum antibiotic with no cross resistance to existing antibiotic classes, and is the first pleuromutilin approved for human use. Like all the pleuromutilins, retapamulin inhibits protein synthesis by binding to domain V of 23S rRNA.

Uses

A broad spectrum antibiotic with no cross resistance to existing classes

Uses

Retapamulin is a semi-synthetic pleuromutilin prepared by reacting pleuromutilin tosylate with tropine-3-thiol to give a more hydrophobic analogue with a tertiary amine. This enables formulation as a stable hydrochloride salt. Retapamulin is a broad spectrum antibiotic with no cross resistance to existing antibiotic classes, and is the first pleuromutilin approved for human use. Like all the pleuromutilins, retapamulin inhibits protein synthesis by binding to domain V of 23S rRNA.

Definition

ChEBI: Retapamulin is a carbotricyclic compound, a carboxylic ester and a cyclic ketone.

brand name

Altabax

Pharmaceutical Applications

A semisynthetic pleuromutilin formulated as a 1% ointment for topical use. It is active against staphylococci (MIC 0.12 mg/L), including methicillin-resistant strains, and against streptococci (MIC 0.03–0.25 mg/L), including Str. pyogenes and Str. pneumoniae. Most enterococci and Gramnegative bacilli are resistant. Propionibacteria are susceptible, suggesting that it might be useful in acne. Early indications suggest that resistance does not emerge readily, but experience with veterinary pleuromutilins indicates that chromosomal resistance may develop with extended use.
It is metabolized in the liver and rapidly excreted, precluding use in systemic infection. Systemic exposure is said to be low following topical application and it appears safe, but there are few data on absorption through broken and unbroken skin. Principal side effects noted include local irritation and occasional allergic reactions. Licensed use is presently restricted to the treatment of impetigo and uncomplicated skin infections. Possible value in methicillin-resistant Staph. aureus (MRSA) infection or carriage has not yet been established.

Side effects

The most frequent adverse event was application site irritation, but other side effects, occurring in o2% of patients, included headache, diarrhea, nausea, and nasopharyngitis. While there are no contraindications, it is recommended that pregnant women only use retapamulin when the potential benefits outweigh the potential risks since animal reproductive studies are not always predictive of human response. Likewise, nursing mothers are cautioned about the unknown possibility of retapamulin excretion in breast milk.

Synthesis

The synthesis of retapamulin begins with generation of the mesylate of pleuromutilin, isolated through fermentation of Clitopilus passeckerianus, followed by nucleophilic substitution with exo-8-methyl-8-azabicyclo[3.2.1]octan-3-thiol under basic conditions Shridhar Hegde and Michelle Schmidt (potassium-tert-butoxide in ethanol or tetrabutylammonium hydrogen sulfate in dichloromethane/water and sodium hydroxide at pH 12.5). The azabicyclic thiol derivative may be prepared via a Mitsunobu reaction between tropine and thioacetic acid.

References

[1] jones r n, fritsche t r, sader h s, et al. activity of retapamulin (sb-275833), a novel pleuromutilin, against selected resistant gram-positive cocci. antimicrobial agents and chemotherapy, 2006, 50(7): 2583-2586.
[2] rittenhouse s, biswas s, broskey j, et al. selection of retapamulin, a novel pleuromutilin for topical use. antimicrobial agents and chemotherapy, 2006, 50(11): 3882-3885.

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