This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Falzari, K.
Right arrow Articles by Franzblau, S. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Falzari, K.
Right arrow Articles by Franzblau, S. G.

 Previous Article  |  Next Article 

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.



This article has been cited by other articles:

  • Cho, S. H., Warit, S., Wan, B., Hwang, C. H., Pauli, G. F., Franzblau, S. G. (2007). Low-Oxygen-Recovery Assay for High-Throughput Screening of Compounds against Nonreplicating Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 51: 1380-1385 [Abstract] [Full Text]  
  • Andini, N., Nash, K. A. (2006). Intrinsic Macrolide Resistance of the Mycobacterium tuberculosis Complex Is Inducible. Antimicrob. Agents Chemother. 50: 2560-2562 [Abstract] [Full Text]  
  • Hoyt, J. C., Ballering, J., Numanami, H., Hayden, J. M., Robbins, R. A. (2006). Doxycycline Modulates Nitric Oxide Production in Murine Lung Epithelial Cells. J. Immunol. 176: 567-572 [Abstract] [Full Text]  
  • Madsen, C. T., Jakobsen, L., Buriankova, K., Doucet-Populaire, F., Pernodet, J.-L., Douthwaite, S. (2005). Methyltransferase Erm(37) Slips on rRNA to Confer Atypical Resistance in Mycobacterium tuberculosis. J. Biol. Chem. 280: 38942-38947 [Abstract] [Full Text]  


Copyright © 2010 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»