Gemfibrozil inhibits Legionella pneumophila and Mycobacterium tuberculosis enoyl coenzyme A reductases and blocks intracellular growth of these bacteria in macrophages

Ronit Reich-Slotky; Christina A. Kabbash; Phyllis Della-Latta; John S. Blanchard; Steven J. Feinmark; Sherry Freeman; Gilla Kaplan; Howard A. Shuman; Samuel C. Silverstein

doi:10.1128/JB.00175-09

Gemfibrozil inhibits Legionella pneumophila and Mycobacterium tuberculosis enoyl coenzyme A reductases and blocks intracellular growth of these bacteria in macrophages

Ronit Reich-Slotky, Christina A. Kabbash, Phyllis Della-Latta, John S. Blanchard, Steven J. Feinmark, Sherry Freeman, Gilla Kaplan, Howard A. Shuman, Samuel C. Silverstein

Biochemistry

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	5262-5271
Number of pages	10
Journal	Journal of Bacteriology
Volume	191
Issue number	16
DOIs	https://doi.org/10.1128/JB.00175-09
State	Published - Aug 2009

ASJC Scopus subject areas

Microbiology
Molecular Biology

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Reich-Slotky, R., Kabbash, C. A., Della-Latta, P., Blanchard, J. S., Feinmark, S. J., Freeman, S., Kaplan, G., Shuman, H. A., & Silverstein, S. C. (2009). Gemfibrozil inhibits Legionella pneumophila and Mycobacterium tuberculosis enoyl coenzyme A reductases and blocks intracellular growth of these bacteria in macrophages. Journal of Bacteriology, 191(16), 5262-5271. https://doi.org/10.1128/JB.00175-09

Gemfibrozil inhibits Legionella pneumophila and Mycobacterium tuberculosis enoyl coenzyme A reductases and blocks intracellular growth of these bacteria in macrophages. / Reich-Slotky, Ronit; Kabbash, Christina A.; Della-Latta, Phyllis; Blanchard, John S.; Feinmark, Steven J.; Freeman, Sherry; Kaplan, Gilla; Shuman, Howard A.; Silverstein, Samuel C.

In: Journal of Bacteriology, Vol. 191, No. 16, 08.2009, p. 5262-5271.

Research output: Contribution to journal › Article › peer-review

Reich-Slotky, R, Kabbash, CA, Della-Latta, P, Blanchard, JS, Feinmark, SJ, Freeman, S, Kaplan, G, Shuman, HA & Silverstein, SC 2009, 'Gemfibrozil inhibits Legionella pneumophila and Mycobacterium tuberculosis enoyl coenzyme A reductases and blocks intracellular growth of these bacteria in macrophages', Journal of Bacteriology, vol. 191, no. 16, pp. 5262-5271. https://doi.org/10.1128/JB.00175-09

Reich-Slotky, Ronit ; Kabbash, Christina A. ; Della-Latta, Phyllis ; Blanchard, John S. ; Feinmark, Steven J. ; Freeman, Sherry ; Kaplan, Gilla ; Shuman, Howard A. ; Silverstein, Samuel C. / Gemfibrozil inhibits Legionella pneumophila and Mycobacterium tuberculosis enoyl coenzyme A reductases and blocks intracellular growth of these bacteria in macrophages. In: Journal of Bacteriology. 2009 ; Vol. 191, No. 16. pp. 5262-5271.

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abstract = "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.",

author = "Ronit Reich-Slotky and Kabbash, {Christina A.} and Phyllis Della-Latta and Blanchard, {John S.} and Feinmark, {Steven J.} and Sherry Freeman and Gilla Kaplan and Shuman, {Howard A.} and Silverstein, {Samuel C.}",

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AU - Kabbash, Christina A.

AU - Della-Latta, Phyllis

AU - Blanchard, John S.

AU - Feinmark, Steven J.

AU - Freeman, Sherry

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AB - 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.

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