This Article Full Text Full Text (PDF) An erratum has been published Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Harth, G. Articles by Horwitz, M. A. Search for Related Content PubMed PubMed Citation Articles by Harth, G. Articles by Horwitz, M. A.

Inhibition of Mycobacterium tuberculosis Glutamine Synthetase as a Novel Antibiotic Strategy against Tuberculosis: Demonstration of Efficacy In Vivo

Department of Medicine, School of Medicine, University of California, Los Angeles, California 90095-1688

Received 6 June 2002/ Returned for modification 8 August 2002/ Accepted 27 September 2002

Tuberculosis remains one of humankind's greatest killers, and new therapeutic strategies are needed to combat the causative agent, Mycobacterium tuberculosis, which is rapidly developing resistance to conventional antibiotics. Using the highly demanding guinea pig model of pulmonary tuberculosis, we have investigated the feasibility of inhibiting M. tuberculosis glutamine synthetase (GS), an enzyme that plays a key role in both nitrogen metabolism and cell wall biosynthesis, as a novel antibiotic strategy. In guinea pigs challenged by aerosol with the highly virulent Erdman strain of M. tuberculosis, the GS inhibitor L-methionine-SR-sulfoximine (MSO) protected the animals against weight loss, a hallmark of tuberculosis, and against the growth of M. tuberculosis in the lungs and spleen; MSO reduced the CFU of M. tuberculosis at 10 weeks after challenge by 0.7 log unit compared with that in control animals. MSO acted synergistically with isoniazid in protecting animals against weight loss and bacterial growth, reducing the CFU in the lungs and spleen by 1.5 log units below the level seen with isoniazid alone. In the presence of ascorbate, which allows treatment with a higher dose, MSO was highly efficacious, reducing the CFU in the lungs and spleen by 2.5 log units compared with that in control animals. This study demonstrates that inhibition of M. tuberculosis GS is a feasible therapeutic strategy against this pathogen and supports the concept that M. tuberculosis enzymes involved in cell wall biosynthesis, including major secretory proteins, have potential as antibiotic targets.

Editor: S. H. E. Kaufmann

This article has been cited by other articles:

• Carroll, P., Pashley, C. A., Parish, T. (2008). Functional Analysis of GlnE, an Essential Adenylyl Transferase in Mycobacterium tuberculosis. J. Bacteriol. 190: 4894-4902 [Abstract] [Full Text]  
• Singh, U., Sarkar, D. (2006). Development of a Simple High-Throughput Screening Protocol Based on Biosynthetic Activity of Mycobacterium tuberculosis Glutamine Synthetase for the Identification of Novel Inhibitors. J Biomol Screen 11: 1035-1042 [Abstract]  
• Singh, U., Panchanadikar, V., Sarkar, D. (2005). Development of a Simple Assay Protocol for High-Throughput Screening of Mycobacterium tuberculosis Glutamine Synthetase for the Identification of Novel Inhibitors. J Biomol Screen 10: 725-729 [Abstract]  
• Krajewski, W. W., Jones, T. A., Mowbray, S. L. (2005). Structure of Mycobacterium tuberculosis glutamine synthetase in complex with a transition-state mimic provides functional insights. Proc. Natl. Acad. Sci. USA 102: 10499-10504 [Abstract] [Full Text]  
• Mehta, R., Pearson, J. T., Mahajan, S., Nath, A., Hickey, M. J., Sherman, D. R., Atkins, W. M. (2004). Adenylylation and Catalytic Properties of Mycobacterium tuberculosis Glutamine Synthetase Expressed in Escherichia coli versus Mycobacteria. J. Biol. Chem. 279: 22477-22482 [Abstract] [Full Text]  
• Smith, I. (2003). Mycobacterium tuberculosis Pathogenesis and Molecular Determinants of Virulence. Clin. Microbiol. Rev. 16: 463-496 [Abstract] [Full Text]  
• Tullius, M. V., Harth, G., Horwitz, M. A. (2003). Glutamine Synthetase GlnA1 Is Essential for Growth of Mycobacterium tuberculosis in Human THP-1 Macrophages and Guinea Pigs. Infect. Immun. 71: 3927-3936 [Abstract] [Full Text]