EFFICACIES OF ABT-719 AND RELATED 2-PYRIDONES, MEMBERS OF A NEW CLASSOF ANTIBACTERIAL AGENTS, AGAINST EXPERIMENTAL BACTERIAL-INFECTIONS

The 2-pyridones are a new class of broad-spectrum orally bioavailable antibacterial agents. These compounds are potent bacterial DNA gyrase inhibitors which differ from fluoroquinolones by placement of the nitr ogen atom in the ring juncture. ABT-719 is an S isomer and a represent ative 2-pyridone. ABT-719 administered orally or subcutaneously was 4- to 10-fold more effective than ciprofloxacin against Staphylococcus a ureus, Streptococcus pneumoniae, and Streptococcus pyogenes infections in normal mice. ABT-719 was equivalent in efficacy to ciprofloxacin f or treatment of gram-negative bacterial infections caused by Pseudomon as aeruginosa or Escherichia coli. The racemate and R forms of ABT-719 were at least threefold lower than those of ciprofloxacin for therapy of intracellular infections caused by Salmonella typhimurium or Liste ria monocytogenes. In immunosuppressed mice, ABT-719 was more effectiv e than ciprofloxacin against quinolone-sensitive S. aureus, Enterococc us faecalis, and Enterococcus faecium. The pharmacokinetic properties of ABT-719 were consistent with its relative efficacy. The 2-pyridone are potent, orally available antibacterial agents with efficacy agains t gram-positive and gram-negative bacterial infections in mice.