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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)5262-5271
Number of pages10
JournalJournal of Bacteriology
Volume191
Issue number16
DOIs
StatePublished - Aug 2009

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acyl-CoA dehydrogenase (NADP+)
Gemfibrozil
Legionella pneumophila
Mycobacterium tuberculosis
Macrophages
Bacteria
Growth
Escherichia coli
Oxidoreductases
Multidrug-Resistant Tuberculosis
Temperature
Fatty Acids

ASJC Scopus subject areas

  • Microbiology
  • Molecular Biology

Cite this

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 journalArticle

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.",
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AU - Blanchard, John S.

AU - Feinmark, Steven J.

AU - Freeman, Sherry

AU - Kaplan, Gilla

AU - Shuman, Howard A.

AU - Silverstein, Samuel C.

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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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