Meropenem-Clavulanate Is Effective Against Extensively Drug-Resistant Mycobacterium tuberculosis

American Association for the Advancement of Science (AAAS) - Tập 323 Số 5918 - Trang 1215-1218 - 2009
Jean‐Emmanuel Hugonnet1,2, L.W. Tremblay1,2, Helena I. Boshoff1,2, Clifton E. Barry1,2, John S. Blanchard1,2
1Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461 USA
2Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA

Tóm tắt

β-lactam antibiotics are ineffective against Mycobacterium tuberculosis , being rapidly hydrolyzed by the chromosomally encoded blaC gene product. The carbapenem class of β-lactams are very poor substrates for BlaC, allowing us to determine the three-dimensional structure of the covalent BlaC-meropenem covalent complex at 1.8 angstrom resolution. When meropenem was combined with the β-lactamase inhibitor clavulanate, potent activity against laboratory strains of M. tuberculosis was observed [minimum inhibitory concentration (MIC meropenem ) less than 1 microgram per milliliter], and sterilization of aerobically grown cultures was observed within 14 days. In addition, this combination exhibited inhibitory activity against anaerobically grown cultures that mimic the “persistent” state and inhibited the growth of 13 extensively drug-resistant strains of M. tuberculosis at the same levels seen for drug-susceptible strains. Meropenem and clavulanate are Food and Drug Administration–approved drugs and could potentially be used to treat patients with currently untreatable disease.

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The authors wish to thank J. Chan and E. Russel for help in the Wayne model studies and H. Xiao for assistance in mass spectrometry. This work was supported partially by the NIH (AI33696 to J.S.B.); in part by the Intramural Research Program of the NIH National Institute of Allergy and Infectious Diseases; and in part by a grant from the Bill and Melinda Gates Foundation and the Wellcome Trust through the Grand Challenges in Global Health Initiative. A provisional U.S. patent application was filed on 27 May 2008 related to this work. Structure coordinates have been deposited as Protein Data Bank identification code 3DWZ.

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American Association for the Advancement of Science (AAAS)

Tập 323 Số 5918

1215-1218

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