EDP-420, a Bicyclolide (Bridged Bicyclic Macrolide), Is Active against Mycobacterium avium

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 μg/ml (MIC 50 of 4 μg/ml and MIC 90 of 8 μg/ml). In macrophages, EDP-420 was inhibitory at 0.5 μg/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 −9 , which is significantly less than the emergence of resistance to clarithromycin, ∼10 −7 ( P