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

Abstract

ABSTRACT 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 < 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, ∼10 −7 ( P < 0.05). Further evaluation of EDP-420 in the treatment of MAC disease is warranted.