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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 polyhydroxy-butyrate. 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 Mycobacterium tuberculosis gene Rv2747 encodes a novel 19-kDa ArgA that catalyzes the initial step in L-arginiue biosynthesis, namely the conversion of L-glutamate to [alpha]-N-acetyl-e-glutamate. Initial velocity studies reveal that Rv2747 proceeds through a sequential kinetic mechanism, with [K.sub.m] values of 280 mM for L-glutamine and 150 [micro]M for acetyl-coenzyme A and with a [k.sub.cat] value of 200 [min.sup.-1]. Initial velocity studies with L-glutamate showed that even at concentrations of 600 mM, saturation was not observed. Therefore, only a [k.sub.cat]/[K.sub.m] value of 125 [M.sup.-1] [min.sup.-1] can be calculated. Inhibition studies reveal that the enzyme is strongly regulated by L-arginine, the end product of the pathway (50% inhibitory concentration, 26 [micro]M). The enzyme was completely inhibited by 500 [micro]M arginine, with a Hill coefficient of 0.60, indicating negatively cooperative binding of L-arginine.