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    • pleuromutilins
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pleuromutilins

Home / pipeline & research / pleuromutilins

Pleuromutilins Are An Investigational Research Focus at Nabriva

Discovered in 1950, pleuromutilins have the potential to be developed as a new class of antibiotics for systemic administration in humans. See what scientists have learned to date about their mechanism of action.


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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.

Our Research Program

At Nabriva, our research program is based on our large and diverse proprietary compound library. We believe that our expertise in the areas of medicinal chemistry, pharmacology, and toxicology have enabled targeted discovery of novel pleuromutilins through modification of side chains and core positions in the mutilin moiety. These modifications have resulted in alterations in microbial activity, ADME, and toxicity of the semi-synthetic molecules.

We are actively pursuing an in-house discovery program to sustain our pipeline with future product candidates. The aim of this program is (1) the development of novel pleuromutilins with enhanced affinity for the bacterial ribosome site where they bind and inhibit bacterial growth, directed at increasing the antimicrobial potency, and (2) broadening the spectrum of activity to include rare strains with known mechanisms of resistance (e.g., cfr or Vga mutants). We believe next-generation pleuromutilins have the potential to exhibit improved antibacterial activity and a pharmacokinetic profile that may make them well suited for the treatment of respiratory tract infections, acute/complicated bacterial skin infections, sexually transmitted infections, and biothreat organisms.

Collaborate With Us

We actively seek collaborators and licensing opportunities focused on the discovery, development, and commercialization of technologies and therapies that address infectious diseases. Contact us to learn more.

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© Nabriva Therapeutics plc, Ireland Registration No. 599588, 25-28 North Wall Quay, Dublin 1, Ireland