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
Services
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 Lenaerts, A. J.
Right arrow Articles by Basaraba, R. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lenaerts, A. J.
Right arrow Articles by Basaraba, R. J.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, September 2007, p. 3338-3345, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.00276-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Location of Persisting Mycobacteria in a Guinea Pig Model of Tuberculosis Revealed by R207910{triangledown}

Anne J. Lenaerts,1* Donald Hoff,1 Sahar Aly,2 Stefan Ehlers,2 Koen Andries,3 Luis Cantarero,4 Ian M. Orme,1 and Randall J. Basaraba1

Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado 80523,1 Molecular Infection Biology, Research Center Borstel, Parkallee 22, D-23845 Borstel, Germany,2 Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium,3 Mycos Research, 520 E. 67th Ave., Loveland, Colorado 805384

Received 23 February 2007/ Returned for modification 6 April 2007/ Accepted 15 May 2007

The lengthy chemotherapy of tuberculosis reflects the ability of a small subpopulation of Mycobacterium tuberculosis bacteria to persist in infected individuals. To date, the exact location of these persisting bacteria is not known. Lung lesions in guinea pigs infected with M. tuberculosis have striking similarities, such as necrosis, mineralization, and hypoxia, to natural infections in humans. Guinea pigs develop necrotic primary lesions after aerosol infection that differ in their morphology compared to secondary lesions resulting from hematogenous dissemination. In infected guinea pigs conventional therapy for tuberculosis during 6 weeks reduced the bacterial load by 1.7 logs in the lungs and, although this completely reversed lung inflammation associated with secondary lesions, the primary granulomas remained largely unaffected. Treatment of animals with the experimental drug R207910 (TMC207) for 6 weeks was highly effective with almost complete eradication of the bacteria throughout both the primary and the secondary lesions. Most importantly, the few remnants of acid-fast bacilli remaining after R207910 treatment were to be found extracellular, in a microenvironment of residual primary lesion necrosis with incomplete dystrophic calcification. This zone of the primary granuloma is hypoxic and is morphologically similar to what has been described for human lung lesions. These results show that this acellular rim may, therefore, be a primary location of persisting bacilli withstanding drug treatment.

* Corresponding author. Mailing address: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523. Phone: (970) 491-3079. Fax: (970) 491-5125. E-mail: lenaerts{at}colostate.edu

{triangledown} Published ahead of print on 21 May 2007.

Antimicrobial Agents and Chemotherapy, September 2007, p. 3338-3345, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.00276-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • van den Boogaard, J., Kibiki, G. S., Kisanga, E. R., Boeree, M. J., Aarnoutse, R. E. (2009). New Drugs against Tuberculosis: Problems, Progress, and Evaluation of Agents in Clinical Development. Antimicrob. Agents Chemother. 53: 849-862 [Full Text]  
  • Converse, P. J., Karakousis, P. C., Klinkenberg, L. G., Kesavan, A. K., Ly, L. H., Allen, S. S., Grosset, J. H., Jain, S. K., Lamichhane, G., Manabe, Y. C., McMurray, D. N., Nuermberger, E. L., Bishai, W. R. (2009). Role of the dosR-dosS Two-Component Regulatory System in Mycobacterium tuberculosis Virulence in Three Animal Models. Infect. Immun. 77: 1230-1237 [Abstract] [Full Text]  
  • Mann, E., Zaunbrecher, M. A, Hitz, K., Churchward, G. (2008). The 52nd Annual Wind River Conference on Prokaryotic Biology--2008. J. Bacteriol. 190: 7871-7875 [Full Text]  
  • Hoff, D. R., Caraway, M. L., Brooks, E. J., Driver, E. R., Ryan, G. J., Peloquin, C. A., Orme, I. M., Basaraba, R. J., Lenaerts, A. J. (2008). Metronidazole Lacks Antibacterial Activity in Guinea Pigs Infected with Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 52: 4137-4140 [Abstract] [Full Text]  
  • Koul, A., Vranckx, L., Dendouga, N., Balemans, W., Van den Wyngaert, I., Vergauwen, K., Gohlmann, H. W. H., Willebrords, R., Poncelet, A., Guillemont, J., Bald, D., Andries, K. (2008). Diarylquinolines Are Bactericidal for Dormant Mycobacteria as a Result of Disturbed ATP Homeostasis. J. Biol. Chem. 283: 25273-25280 [Abstract] [Full Text]  
  • Rustomjee, R., Diacon, A. H., Allen, J., Venter, A., Reddy, C., Patientia, R. F., Mthiyane, T. C. P., De Marez, T., van Heeswijk, R., Kerstens, R., Koul, A., De Beule, K., Donald, P. R., McNeeley, D. F. (2008). Early Bactericidal Activity and Pharmacokinetics of the Diarylquinoline TMC207 in Treatment of Pulmonary Tuberculosis. Antimicrob. Agents Chemother. 52: 2831-2835 [Abstract] [Full Text]  
  • Park, B., Subbian, S., El-Etr, S. H., Cirillo, S. L. G., Cirillo, J. D. (2008). Use of Gene Dosage Effects for a Whole-Genome Screen To Identify Mycobacterium marinum Macrophage Infection Loci. Infect. Immun. 76: 3100-3115 [Abstract] [Full Text]  
  • Lounis, N., Gevers, T., Van Den Berg, J., Verhaeghe, T., van Heeswijk, R., Andries, K. (2008). Prevention of Drug Carryover Effects in Studies Assessing Antimycobacterial Efficacy of TMC207. J. Clin. Microbiol. 46: 2212-2215 [Abstract] [Full Text]  
  • Via, L. E., Lin, P. L., Ray, S. M., Carrillo, J., Allen, S. S., Eum, S. Y., Taylor, K., Klein, E., Manjunatha, U., Gonzales, J., Lee, E. G., Park, S. K., Raleigh, J. A., Cho, S. N., McMurray, D. N., Flynn, J. L., Barry, C. E. III (2008). Tuberculous Granulomas Are Hypoxic in Guinea Pigs, Rabbits, and Nonhuman Primates. Infect. Immun. 76: 2333-2340 [Abstract] [Full Text]  
  • Ly, L. H., Russell, M. I., McMurray, D. N. (2008). Cytokine Profiles in Primary and Secondary Pulmonary Granulomas of Guinea Pigs with Tuberculosis. Am. J. Respir. Cell Mol. Bio. 38: 455-462 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»