Gemfibrozil inhibits Legionella pneumophila and Mycobacterium tuberculosis enoyl coenzyme A reductases and blocks intracellular growth of these bacteria in macrophages.
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.
Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, NY 10032, USA.
Ronit
R
Reich-Slotky
Christina A
CA
Kabbash
Phyllis
P
Della-Latta
John S
JS
Blanchard
Steven J
SJ
Feinmark
Sherry
S
Freeman
Gilla
G
Kaplan
Howard A
HA
Shuman
Samuel C
SC
Silverstein
D044944:Acyl-CoA Dehydrogenases / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D002995:Clofibric Acid / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D015248:Gemfibrozil / Q000494:pharmacology*; D005985:Glyceraldehyde / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D016952:Legionella pneumophila / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development / Q000648:ultrastructure; D050356:Lipid Metabolism / Q000187:drug effects; D008264:Macrophages / Q000382:microbiology*; D051379:Mice; D008826:Microbial Sensitivity Tests; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D011407:Propane / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid
C047158:3-hydroxypropionaldehyde; D005985:Glyceraldehyde; D002995:Clofibric Acid; D044944:Acyl-CoA Dehydrogenases; C100154:acyl-CoA dehydrogenase (NADP+); D015248:Gemfibrozil; D011407:Propane