title: EDP-420, a bicyclolide (bridged bicyclic macrolide), is active against Mycobacterium avium.
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 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.
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, 101 Magruder Hall, Oregon State University, Corvallis, OR 97331-4802, USA. luiz.bermudez@oregonstate.edu
authors.forename: Luiz E
authors.initials: LE
authors.lastname: Bermudez
authors.forename: Nima
authors.initials: N
authors.lastname: Motamedi
authors.forename: Christopher
authors.initials: C
authors.lastname: Chee
authors.forename: Gyulnar
authors.initials: G
authors.lastname: Baimukanova
authors.forename: Peter
authors.initials: P
authors.lastname: Kolonoski
authors.forename: Clark
authors.initials: C
authors.lastname: Inderlied
authors.forename: Priscilla
authors.initials: P
authors.lastname: Aralar
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Wang
authors.forename: Ly Tam
authors.initials: LT
authors.lastname: Phan
authors.forename: Lowell S
authors.initials: LS
authors.lastname: Young
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial; D005260:Female; D006801:Humans; D018942:Macrolides / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D009162:Mycobacterium avium / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D001952:Bridged-Ring Compounds; C520838:EDP 420; D018942:Macrolides