bOmadacycline is a novel first-in-class aminomethylcycline with potent activity against important skin and pneumonia pathogens, including community-acquired methicillin-resistant Staphylococcus aureus (MRSA), -hemolytic streptococci, penicillinresistant Streptococcus pneumoniae, Haemophilus influenzae, and Legionella. 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 active in vitro in the presence of the ribosomal protection protein Tet(O).
Omadacycline is the first of the novel aminomethylcyclines, which are semisynthetic compounds related to the tetracyclines, to undergo clinical development (Fig. 1). The tetracycline family of antimicrobials has been in clinical use for over 60 years and includes tetracycline, doxycycline, and minocycline. As a class, they are well tolerated; have a broad spectrum of antimicrobial activity, including against Gram-positive bacteria, Gram-negative bacteria, anaerobes, and atypical bacteria; and have proven effective in the treatment of a variety of bacterial infections involving respiratory tract, skin and skin structure, urinary tract, and intra-abdominal sites (1, 2).When first released in the 1950s to 1960s, the tetracyclines were an important component of the antibiotic armamentarium. Their clinical use declined in subsequent years, primarily due to the increasing prevalence of tetracycline resistance and the availability of effective alternative therapies. There are two major mechanisms of tetracycline resistance: efflux and ribosome protection. The two mechanisms have been described in Gram-positive and Gram-negative bacteria either separately or together, with ribosome protection generally more common in Gram-positive bacteria and efflux in Gram-negative bacteria (3). The most common genotypes of ribosome protection are tet(M) and tet(O). Efflux is determined by a family of related genotypes, in particular, tet(K) and tet(B) (2).Omadacycline has potent activity against important skin and lung pathogens, including community-acquired methicillin-resistant Staphylococcus aureus (MRSA), -hemolytic streptococci, penicillin-resistant Streptococcus pneumoniae, Haemophilus influenzae, and Legionella. The compound specifically overcomes tetracycline resistance mechanisms and is not affected by mechanisms of resistance to other classes of antibiotics. Omadacycline is entering phase 3 development for treatment of acute bacterial skin and skin structure infections (ABSSSI), community-acqu...