Fatty acid biosynthesis is essential for bacterial survival. Components of this biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. FabH, beta-ketoacyl-ACP synthase III, is a particularly attractive target, since it is central to the initiation of fatty acid biosynthesis and is highly conserved among Gram-positive and -negative bacteria. Small molecules that inhibit FabH enzymatic activity have the potential to be candidates within a novel class of selective, nontoxic, broad-spectrum antibacterials. Using crystallographic structural information on these highly conserved active sites and structure based drug design principles, a benzoylaminobenzoic acid series of compounds was developed as potent inhibitors of FabH. This inhibitor class demonstrates strong antibacterial activity against Gram-positive and selected Gram-negative organisms.

a b s t r a c tFabH (b-ketoacyl-acyl carrier protein synthase III) is unique in that it initiates fatty acid biosynthesis, is inhibited by long-chain fatty acids providing means for feedback control of the process, and dictates the fatty acid profile of the organism by virtue of its substrate specificity. We report the crystal structures of bacterial FabH enzymes from four different pathogenic species: Enterococcus faecalis, Haemophilus influenzae, Staphylococcus aureus and Escherichia coli. Structural data on the enzyme from different species show important differences in the architecture of the substratebinding sites that parallel the inter-species diversity in the substrate specificities of these enzymes.

This investigation was undertaken to determine the role of beta-adrenergic receptors in the regulation of the protein composition of rat parotid saliva. Chronic treatment of rats with dobutamine, a beta 1-adrenergic agonist, resulted in changes in parotid saliva volume, protein concentration, and composition which were essentially the same as those changes which occurred following chronic treatment with isoproterenol, a non-specific beta-adrenergic agonist. Chronic treatment with the beta 2-adrenergic agonist, terbutaline, had no effect on parotid saliva volume, protein concentration, or composition. Chronic treatment of rats with a beta 1-adrenergic antagonist, metoprolol, had different effects on saliva dependent on the manner by which the drug was delivered. Twice-daily injections of metoprolol led to a decrease in flow rate, but protein concentration and composition were unaltered. When metoprolol was delivered by surgically implanted osmotic minipumps, neither the flow of parotid saliva nor its concentration of protein was altered; however, there was a reduction in the proportion of proline-rich proteins in saliva. Comparable changes in parotid saliva protein composition occurred when the minipumps delivered propranolol, a non-specific beta-adrenergic antagonist. Chronic treatment of rats with an alpha 2-adrenergic agonist (clonidine) or antagonist (yohimbine) was without effect on parotid saliva flow rate, protein concentration, or composition. These findings suggest that the synthesis of proline-rich proteins is regulated, in part, by beta-adrenergic receptor stimulation, and primarily by the beta 1-receptor subtype.

Previous studies have indicated that adrenal-intact rats treated for one week with pharmacological doses of the synthetic glucocorticoid, dexamethasone, show a significant reduction in the proportion of proline-rich proteins and an increase in the proportion of amylase in rat parotid saliva (Johnson et al., 1987). In order to understand more fully the role of glucocorticoids in the regulation of salivary proteins, we performed bilateral adrenalectomies on groups of rats. Some of the adrenalectomized rats were treated with replacement-level doses of the synthetic glucocorticoid, dexamethasone. The food intake was monitored daily for both groups, and sham-operated pair-fed controls were included so that the effects of alterations of food intake could be separated from those of the experimental procedures. After eight to 12 days, uniformly stimulated parotid saliva was collected from these animals as well as from sham-operated controls fed ad libitum. The volume of saliva collected in 30 min was recorded, and the saliva samples were analyzed for concentration and composition of protein. Although the volume of saliva was not affected, parotid saliva collected from adrenalectomized rats exhibited a two-fold greater proportion of proline-rich proteins and reductions in other major secretory proteins: DNase, Fraction I, and Fraction V. The parotid gland secretory granules of adrenalectomized rats were more electron-lucent than in the ad libitum-fed controls. Treatment of adrenalectomized rats with dexamethasone largely prevented the changes in salivary protein composition as well as the alterations in secretory granule morphology.(ABSTRACT TRUNCATED AT 250 WORDS)

No abstract