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JAC Advance Access originally published online on August 18, 2004
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Journal of Antimicrobial Chemotherapy 2004 54(4):824-827; doi:10.1093/jac/dkh402
JAC vol.54 no.4 © The British Society for Antimicrobial Chemotherapy 2004; all rights reserved

Antimycobacterial activity of synthetic pamamycins

P. Lefèvre1, P. Peirs1, M. Braibant1,*, M. Fauville-Dufaux1, R. Vanhoof1, K. Huygen1, X.-M. Wang1, B. Pogell2, Y. Wang3, P. Fischer3, P. Metz3 and J. Content1,{dagger}

1 Institut Pasteur de Bruxelles, 642, rue Engeland, B-1180, Brussels, Belgium; 2 University of Maryland Biotechnology Institute, College Park, MD 20742, USA; 3 Technische Universität Dresden, Institut für Organische Chemie, Bergstraße 66, D-01069, Dresden, Germany

{dagger} Corresponding author. Tel: +32-2-373-416; Fax: +32-2-373-3291; Email: jcontent{at}pasteur.be

Objectives: Early studies have indicated that pamamycins, a group of macrodiolides first isolated from Streptomyces alboniger, have potent antimicrobial activity against Gram-positive bacteria, fungi and mycobacteria but not against Gram-negative bacteria. The recent availability of highly purified and reasonable quantities of several pamamycins through their total syntheses has rendered possible more extensive studies on their effects on mycobacteria.

Methods: Bioluminescent strains of Mycobacterium tuberculosis, Mycobacterium bovis BCG and Mycobacterium smegmatis, expressing the luxA and luxB genes from Vibrio harveyi were used for the comparison of the antimycobacterial activity of the two synthetic macrodiolides pamamycin-607 and pamamycin-621A and a non-naturally occurring cyclic dimer of pamamycin-607, i.e. yukomycin.

Results: Pamamycin-607 was the most active of the three macrocycles and was more active against M. tuberculosis than against M. smegmatis. Twenty-five clinical isolates of M. tuberculosis were susceptible to pamamycin-607 in a narrow MIC range of 1.5–2.0 mg/L. The new assay was also validated by comparison with the BACTEC radiometric test.

Conclusion: Rapid screening of a new class of macrocyclic antimycobacterials using bioluminescent mycobacteria identified pamamycin-607 as a potential antituberculous agent. The latter was active against clinical isolates of M. tuberculosis within a narrow MIC range of 1.5–2.0 mg/L irrespective of their resistance to isoniazid or rifampicin. Our findings warrant further investigations.

Keywords: bioluminescence , luciferase , Mycobacterium tuberculosis , macrodiolides


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