Antibiotics inhibit bacterial replication by inhibiting cell wall synthesis, disrupting cell wall integrity, or interfering with DNA function, folate metabolism, or protein synthesis.
Bacterial protein synthesis involves ribosomal subunits binding to messenger RNA in the peptidyl transferase center, or the PTC, at 3 active sites: the A, P, and E sites. As the first transfer RNA enters the PTC with its amino acid, another transfer RNA migrates adjacent to it. The ribosome then links the amino acid chain.
Pleuromutilins are a new class of systemic antibiotics being studied for human use with a novel mechanism of action that results in disruption of ribosomal protein synthesis. Pleuromutilins bind to the 50-S subunit of the bacterial ribosome at a highly conserved region on the PTC, via multiple interactions. The tricyclic core positions centrally at the PTC pocket close to the A site, whereas the C-14 side chain extends towards the P site, causing steric interference with ribosomal nucleotides, which consequently interact with each other. This results in the closing of the ribosomal binding pocket around the pleuromutilin and tightens binding between the pleuromutilin and the ribosome. In vitro and crystallography work have indicated where antibiotic classes are believed to bind around the PTC, which differs from the binding sites of the pleuromutilins.
The antibacterial spectrum of activity of the pleuromutilins is targeted to Gram-positive, Gram-negative, and atypical pathogens commonly associated with community-acquired respiratory infections, including multi-drug—resistant strains, and skin and skin structure infections caused by Streptococcus and Staphylococcus species, including MRSA. Noteably, the in vitro activity of the pleuromutilins does not include normal flora of the gastrointestinal tract, including B. fragilis, E. coli, and E. faecalis.
Despite decades of pleuromutilin therapeutic use in the treatment of livestock infections, the incidence of pleuromutilin-resistant isolates remains rare. It is believed the pleuromutilins’ novel mechanism of action results in a low propensity for the development of resistance, as in vitro studies have demonstrated a mutation frequency of 10-9 to 10-12 and rare cross-resistance to other antibiotic classes.