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Journal of Bacteriology, August 2009, p. 5262-5271, Vol. 191, No. 16
0021-9193/09/$08.00+0     doi:10.1128/JB.00175-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Gemfibrozil Inhibits Legionella pneumophila and Mycobacterium tuberculosis Enoyl Coenzyme A Reductases and Blocks Intracellular Growth of These Bacteria in Macrophages{triangledown}

Ronit Reich-Slotky,1 Christina A. Kabbash,4 Phyllis Della-Latta,3 John S. Blanchard,6 Steven J. Feinmark,5 Sherry Freeman,7 Gilla Kaplan,7 Howard A. Shuman,2 and Samuel C. Silverstein1*

Department of Physiology & Cellular Biophysics,1 Department of Microbiology,2 Department of Clinical Microbiology,3 Integrated Program in Cellular, Molecular, and Biophysical Studies,4 Department of Pharmacology, Columbia University Medical Center, New York, New York 10032,5 Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461,6 Laboratory of Mycobacterial Immunity and Pathogenesis, Public Health Research Institute Center at the University of Medicine and Dentistry of New Jersey, Newark, New Jersey 071037

Received 9 February 2009/ Accepted 30 April 2009

We report here that gemfibrozil (GFZ) inhibits axenic and intracellular growth of Legionella pneumophila and of 27 strains of wild-type and multidrug-resistant Mycobacterium tuberculosis in bacteriological medium and in human and mouse macrophages, respectively. At a concentration of 0.4 mM, GFZ completely inhibited L. pneumophila fatty acid synthesis, while at 0.12 mM it promoted cytoplasmic accumulation of polyhydroxybutyrate. To assess the mechanism(s) of these effects, we cloned an L. pneumophila FabI enoyl reductase homolog that complemented for growth an Escherichia coli strain carrying a temperature-sensitive enoyl reductase and rendered the complemented E. coli strain sensitive to GFZ at the nonpermissive temperature. GFZ noncompetitively inhibited this L. pneumophila FabI homolog, as well as M. tuberculosis InhA and E. coli FabI.

* Corresponding author. Mailing address: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, 630 W 168th St., P&S11-444, New York, NY 10032. Phone: (212) 305-3546. Fax: (212) 305-5775. E-mail: scs3{at}columbia.edu

{triangledown} Published ahead of print on 1 May 2009.

Journal of Bacteriology, August 2009, p. 5262-5271, Vol. 191, No. 16
0021-9193/09/$08.00+0     doi:10.1128/JB.00175-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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