Mechanism of Action of the Novel Aminomethylcycline Antibiotic Omadacycline

Abstract

ABSTRACTOmadacycline is a novel first-in-class aminomethylcycline with potent activity against important skin and pneumonia pathogens, including community-acquired methicillin-resistantStaphylococcus aureus(MRSA), β-hemolytic streptococci, penicillin-resistantStreptococcus pneumoniae,Haemophilus influenzae, andLegionella. In this work, the mechanism of action for omadacycline was further elucidated using a variety of models. Functional assays demonstrated that omadacycline is active against strains expressing the two main forms of tetracycline resistance (efflux and ribosomal protection). Macromolecular synthesis experiments confirmed that the primary effect of omadacycline is on bacterial protein synthesis, inhibiting protein synthesis with a potency greater than that of tetracycline. Biophysical studies with isolated ribosomes confirmed that the binding site for omadacycline is similar to that for tetracycline. In addition, unlike tetracycline, omadacycline is activein vitroin the presence of the ribosomal protection protein Tet(O).