Infection caused by Mycobacterium avium complex (MAC) is common in patients with immunosuppression, such as AIDS, and deficiencies of gamma interferon and interleukin-12, as well as patients with chronic lung diseases. Treatment of MAC disease is limited since few drugs show in vivo activity. We tested a new bridged bicyclic macrolide, EDP-420, against MAC in vitro and in beige mice. EDP-420 was inhibitory in vitro at a concentration ranging from 2 to 8 microg/ml (MIC(50) of 4 microg/ml and MIC(90) of 8 microg/ml). In macrophages, EDP-420 was inhibitory at 0.5 microg/ml, suggesting that the drug concentrates intracellularly. Mice infected with macrolide-susceptible MAC strain 101 were given 100 mg of EDP-420/kg of body weight daily for 4 weeks and showed a significant reduction in the number of bacteria in both liver and spleen which was greater than the reduction observed with clarithromycin treatment at the same dose (P < 0.05). However, macrolide-resistant MAC 101 did not respond to EDP-420 treatment. A combination of EDP-420 with mefloquine was shown to be indifferent; mefloquine alone was active against macrolide-resistant MAC. The frequency of resistance to EDP-420 in MAC 101 was 10(-9), which is significantly less than the emergence of resistance to clarithromycin, approximately 10(-7) (P < 0.05). Further evaluation of EDP-420 in the treatment of MAC disease is warranted.