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Antimicrobial Agents and Chemotherapy, April 2005, p. 1447-1454, Vol. 49, No. 4
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.4.1447-1454.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

In Vitro and In Vivo Activities of Macrolide Derivatives against Mycobacterium tuberculosis

Kanakeshwari Falzari,1 Zhaohai Zhu,1 Dahua Pan,1 Huiwen Liu,1 Poonpilas Hongmanee,2 and Scott G. Franzblau1*

Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois,1 Department of Pathology, Faculty of Medicine, Ramathibodhi Hospital, Bangkok, Thailand2

Received 15 July 2004/ Returned for modification 6 August 2004/ Accepted 22 October 2004

Existing macrolides have never shown definitive clinical efficacy in tuberculosis. Recent reports suggest that ribosome methylation is involved in macrolide resistance in Mycobacterium tuberculosis, a mechanism that newer macrolides have been designed to overcome in gram-positive bacteria. Therefore, selected macrolides and ketolides (descladinose) with substitutions at positions 9, 11,12, and 6 were assessed for activity against M. tuberculosis, and those with MICs of ≤4 µM were evaluated for cytotoxicity to Vero cells and J774A.1 macrophages. Several compounds with 9-oxime substitutions or aryl substitutions at position 6 or on 11,12 carbamates or carbazates demonstrated submicromolar MICs. For the three macrolide-ketolide pairs, macrolides demonstrated superior activity. Four compounds with low MICs and low cytotoxicity also effected significant reductions in CFU in infected macrophages. Active compounds were assessed for tolerance and the ability to reduce CFU in the lungs of BALB/c mice in an aerosol infection model. A substituted 11,12 carbazate macrolide demonstrated significant dose-dependent inhibition of M. tuberculosis growth in mice, with a 10- to 20-fold reduction of CFU in lung tissue. Structure-activity relationships, some of which are unique to M. tuberculosis, suggest several synthetic directions for further improvement of antituberculosis activity. This class appears promising for yielding a clinically useful agent for tuberculosis.

* Corresponding author. Mailing address: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St., MC 964, Rm. 412, Chicago, IL 60612-7231. Phone: (312) 355-1715. Fax: (312) 355-2693. E-mail: sgf{at}uic.edu.

Antimicrobial Agents and Chemotherapy, April 2005, p. 1447-1454, Vol. 49, No. 4
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.4.1447-1454.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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