Repositioning Candidate Details

Candidate ID: R1464
Source ID: DB12825
Source Type: approved; investigational
Compound Type: small molecule
Compound Name: Lefamulin
Synonyms: Lefamulin
Molecular Formula: C28H45NO5S
SMILES: [H][C@@]12C(=O)CC[C@]11CCC(C)[C@@]2(C)[C@@H](C[C@@](C)(C=C)[C@@H](O)[C@@H]1C)OC(=O)CS[C@@H]1CC[C@@H](N)C[C@H]1O
Structure:
DrugBank Description: Lefamulin is a pleuromutilin antibiotic used for the treatment of bacterial community-acquired pneumonia. A pleuromotilin is a more recently developed type of antibiotic that is derived from the fungus, Pleurotus mutilus. Lefamulin is available in intravenous and oral preparations and was granted FDA approval in August 2019. This drug is the first semi-synthetic pleuromutilin that has been designed for systemic administration. Lefamulin features a novel mechanism of action that shows benefit against resistant bacteria that cause pneumonia. The chemical structure of lefamulin contains a tricyclic mutilin core that is necessary for some of its antimicrobial activity.
CAS Number: 1061337-51-6
Molecular Weight: 507.73
DrugBank Indication: Lefamulin is indicated to treat adults diagnosed with community-acquired bacterial pneumonia (CABP) that is caused by susceptible bacteria. Its use should be reserved for confirmed susceptible organisms or a high probability of infection with susceptible organisms. The list of susceptible bacteria includes Streptococcus pneumoniae, Staphylococcus aureus (methicillin-susceptible), Legionella pneumophila, Haemophilus influenza, Chlamydophila pneumoniae, and Mycoplasma pneumoniae.
DrugBank Pharmacology: Lefamulin demonstrates strong antibacterial activity against several microbes that are found to be common in both acute bacterial skin and skin structure infections as well as community-acquired bacterial pneumonia. It shows antibacterial activity against gram-positive and atypical microbes (for example, Streptococcus pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae, Haemophilus influenzae, and Chlamydophila pneumoniae). Lefamulin also exerts activity against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus faecium. It does not treat Pseudomonas aeruginosa infections. During in vitro studies, drug has also has demonstrated activity against Neisseria gonorrhoeae and Mycoplasma genitalium. **A note on QT prolongation and Clostridium difficile** According to the FDA label, lefamulin may have cardiac QT interval prolonging effects and advises against the administration of this drug in patients with diagnosed QT prolongation or ventricular arrhythmias. The administration of lefamulin should also be avoided in patients being administered antiarrhythmic agents and other drugs that prolong the QT interval. As with other antibiotics, the risk of Clostridium difficile associated diarrhea is increased with lefamulin use. Any case of diarrhea should be evaluated for C. difficile.
DrugBank MoA: Lefamulin inhibits prokaryotic ribosomal protein synthesis via its binding to the peptidyl transferase center (PTC) of the ribosomal bacterial 50S subunit. It inhibits protein translation through binding to both the A and P sites of the PTC via four hydrogen bonds, resulting in the interruption of peptide bond formation. Lefamulin's tricyclic mutilin core is the common moiety for binding of all members of its drug class, the pleuromutilins. Although the tricyclic motilin core doesn’t form any hydrogen bonds with the PTC nucleotides, it is stabilized or anchored by hydrophobic and Van der Waals interactions. Lefamulin exerts a selective inhibition of protein translation in eukaryotes, however, does not affect ribosomal translation of eukaryotes. Lefamulin demonstrates a unique induced-fit type of action that closes the binding pocket within a ribosome, conferring close contact of the drug to its target, therefore improving therapeutic efficacy. Because of its mechanism of action that differs from that of other antimicrobials, cross-resistance to other antibiotic classes is less likely.
Targets: 50S ribosomal protein L22 binder
Inclusion Criteria: Indication associated