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

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.The advent of AIDS and the emergence of many multidrugresistant bacterial species have led to renewed efforts to find new antibiotics. The most commonly used antibiotics act by blocking bacterium-specific DNA, RNA, or protein synthesis. Mycobacterium tuberculosis is a major exception to this generalization. While streptomycin, an inhibitor of bacterial protein synthesis, was the first antibiotic to be used successfully to treat M. tuberculosis, isoniazid (INH), an inhibitor of mycobacterial lipid synthesis, is presently the drug most commonly used to treat infections with this organism (2, 43). The differential sensitivity to INH of M. tuberculosis versus mammalian cells reflects the fact that most bacterial fatty acid synthases (type II synthases) are comprised of discrete, separable enzymes encoded by separate genes, while mammalian fatty acid synthases (type I) are dimeric proteins in which a single polypeptide catalyzes the seven enzymatic activities of fatty acid synthesis (21, 52).In previous studies (45), we reported that gemfibrozil (GFZ), a commonly prescribed and well-tolerated hypolipidemic drug, inhibits the export of various organic anions, including penicillin and fluoroquinolones, from murine macrophages, thereby elevating the intracellular concentration of these antibiotics and enhancing their capacity to block intracellular growth of Listeria monocytogenes. In exploring this system, we discovered that while GFZ has no effect on axenic or intracellular growth of Listeria monocytogenes, it inhibits axenic growth of all Legionella pneumophila strains tested and of 5 wild-type and 22 multidrug-resistant strains of M. tuberculosis and inhibits intracellular growth of L. pneumophila Philadelphia-1 and M. tuberculosis H37RV in human and mouse macrophages, respectively.Both M. tuberculosis and L. pneumophila are facultative intracellular pathogens that enter host macrophages by phagocytosis (25, 26), grow in nonlysosomal membrane-bound cytoplasmic vacuoles (24), have special nutrient requirements (38, 54, 55), and produce a relatively unique spectrum of membrane lipids (7, 57). However, M. tuberculosis is a slow-growing and dangerous organism with which to work. In cont...

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“…We found that GEM was effective against Mabc infection in vivo using mouse model. A prior study reported the antimycobacterial activity of GEM in bacteriological medium and in macrophages [54]. Importantly, we found that GEM did not exert a direct antimycobacterial effect against Mabc.…”

Metatranscriptomic Analysis of the Response of River Biofilms to Pharmaceutical Products, Using Anonymous DNA Microarrays

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Effects of Lipid-Lowering Drugs on Vancomycin Susceptibility of Mycobacteria

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