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Antimicrobial Agents and Chemotherapy, May 2007, p. 1666-1670, Vol. 51, No. 5
0066-4804/07/$08.00+0     doi:10.1128/AAC.01303-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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

Luiz E. Bermudez,^1,2* Nima Motamedi,¹ Christopher Chee,¹ Gyulnar Baimukanova,¹ Peter Kolonoski,¹ Clark Inderlied,⁴ Priscilla Aralar,⁴ Guoqiang Wang,³ Ly Tam Phan,³ and Lowell S. Young¹

Kuzell Institute for Arthritis & Infectious Diseases at California Pacific Medical Center Research Institute, San Francisco, California,¹ Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, Oregon,² Enanta Pharmaceuticals, Inc., Watertown, Massachusetts,³ Children's Hospital Los Angeles, Los Angeles, California⁴

Received 18 October 2006/ Returned for modification 21 November 2006/ Accepted 3 February 2007

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 (MIC₅₀ of 4 µg/ml and MIC₉₀ 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.

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* Corresponding author. Mailing address: Department of Biomedical Sciences, College of Veterinary Medicine, 101 Magruder Hall, Oregon State University, Corvallis, OR 97331-4802. Phone: (541) 737-6538. Fax: (541) 737-8035. E-mail: luiz.bermudez{at}oregonstate.edu

Published ahead of print on 12 February 2007.

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Antimicrobial Agents and Chemotherapy, May 2007, p. 1666-1670, Vol. 51, No. 5
0066-4804/07/$08.00+0     doi:10.1128/AAC.01303-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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