Lefamulin

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.