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# Pleuromutilins

Fungus-derived antibiotics that block the peptidyl transferase centre of the 50S ribosome; lefamulin treats community-acquired pneumonia.

Updated Nov 1, 2026

## What they are

Semisynthetic derivatives of pleuromutilin, a natural product of Pleurotus fungi discovered in the 1950s and first used in veterinary medicine. Two are used in humans: retapamulin, topical for impetigo, and lefamulin, oral and intravenous, the first systemic member of the class.

## Mechanism of action

They bind the 50S subunit near the A and P sites of the peptidyl transferase centre; the pocket closes around the drug and transfer RNA cannot settle, so no peptide bond forms. The site partly overlaps those of other 50S inhibitors, but the binding mode is unique and cross-resistance is uncommon.

Target: Peptidyl transferase centre of the 50S ribosomal subunit (23S rRNA, A and P sites)

## Key points

- They cover the typical and atypical community pneumonia pathogens: pneumococcus, H. influenzae, Mycoplasma, Legionella and Chlamydophila.
- Useless against Enterobacterales, Pseudomonas, Acinetobacter and Enterococcus faecalis.
- Lefamulin is metabolised by CYP3A4: strong inducers and inhibitors change its levels.
- Lefamulin prolongs the QT interval and is avoided in pregnancy because of malformations in animals.
- Retapamulin is topical only (impetigo).

## Drugs in this class

- [**Lefamulin** First systemic pleuromutilin, oral or IV, for community-acquired pneumonia: covers pneumococcus and atypicals… Bacterial ribosome, 50S subunit (peptidyl transferase centre)](https://durgical.com/en/pharmacology/lefamulin/)

## Others in the class

- retapamulin

## Test yourself

Think of the answer, then tap the question to see it.

## Which step of protein synthesis do pleuromutilins block?

Peptide bond formation at the peptidyl transferase centre of the 50S subunit.

## What is the only systemic pleuromutilin for humans, and what is it used for?

Lefamulin, for community-acquired bacterial pneumonia in adults.

## Why does lefamulin not work for an E. coli urinary infection?

Pleuromutilins have no useful activity against Enterobacterales.

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Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: [Lefamulin: MedlinePlus Drug Information](https://medlineplus.gov/druginfo/meds/a619059.html) (MedlinePlus (U.S. National Library of Medicine), 2026).

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