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J. Biol. Chem., Vol. 281, Issue 24, 16691-16699, June 16, 2006

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Metalloprotease Inhibitors GM6001 and TAPI-0 Inhibit the Obligate Intracellular Human Pathogen Chlamydia trachomatis by Targeting Peptide Deformylase of the Bacterium^*

Amit Balakrishnan, Bhairavi Patel, Stephan A. Sieber^¶, Ding Chen^||, Niseema Pachikara, Guangming Zhong^||, Benjamin F. Cravatt^¶, and Huizhou Fan¹

From the Robert Wood Johnson Medical School and Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey 08854, ^¶The Scripps Research Institute, La Jolla, California 92037, and the ^||University of Texas Health Science Center, San Antonio, Texas 78229

Chlamydia trachomatis is an obligate intracellular bacterium responsible for a number of human diseases. The mechanism underlying the intracellular parasitology of Chlamydiae remains poorly understood. In searching for host factors required for chlamydial infection, we discovered that C. trachomatis growth was effectively inhibited with GM6001 and TAPI-0, two compounds known as specific inhibitors of matrix metalloproteases. The inhibition was independent of chlamydial entry of the cell, suggesting that the loss of extracellular metalloprotease activities of the host cell is unlikely to be the mechanism for the growth suppression. Nucleotide sequences of candidate metalloprotease genes remained unchanged in a chlamydial variant designated GR10, which had been selected for resistance to the inhibitors. Nevertheless, GR10 displayed a single base mutation in the presumable promoter region of the gene for peptide deformylase (PDF), a metal-dependent enzyme that removes the N-formyl group from newly synthesized bacterial proteins. The mutation correlated with an increased PDF expression level and resistance to actinonin, a known PDF inhibitor with antibacterial activity, as compared with the parental strain. Recombinant chlamydial PDF was covalently labeled with a hydroxamate-based molecular probe designated AspR1, which was developed for the detection of metalloproteases. The AspR1 labeling of the chlamydial PDF became significantly less efficient in the presence of excessive amounts of GM6001 and TAPI-0. Finally, the PDF enzyme activity was efficiently inhibited with GM6001 and TAPI-0. Taken together, our results suggest that the metalloprotease inhibitors suppress chlamydial growth by targeting the bacterial PDF. These findings have important biochemical and medical implications.

Received for publication, December 22, 2005 , and in revised form, March 21, 2006.

^* This work was supported in part by grants from the University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School, the National Center of the American Heart Association (Grant 0330335N), and the National Institutes of Health Grant 1R21AI064441 (to H. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Physiology and Biophysics, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 683 Hoes Lane, Piscataway, NJ 08854. Tel.: 732-235-4607; Fax: 732-235-5823; E-mail: fanhu{at}umdnj.edu.

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