Methicillin-resistant Staphylococcus aureus infection can be treated effectively by combining a β-lactam antibiotic with a drug that targets FtsZ.

No abstract

The potential use of SCD inhibitors for the chronic treatment of diabetes and dyslipidemia has been limited by preclinical adverse events associated with inhibition of SCD in skin and eye tissues. To establish a therapeutic window, we embarked on designing liver-targeted SCD inhibitors by utilizing molecular recognition by liver-specific organic anion transporting polypeptides (OATPs). In doing so, we set out to target the SCD inhibitor to the organ believed to be responsible for the therapeutic efficacy (liver) while minimizing its exposure in the tissues associated with mechanism-based SCD depletion of essential lubricating lipids (skin and eye). These efforts led to the discovery of MK-8245 (7), a potent, liver-targeted SCD inhibitor with preclinical antidiabetic and antidyslipidemic efficacy with a significantly improved therapeutic window.

Protein tyrosine phosphatase 1B (PTP1B) has been implicated in the regulation of the insulin signaling pathway and represents an attractive target for the design of inhibitors in the treatment of type 2 diabetes and obesity. Inspection of the structure of PTP1B indicates that potent PTP1B inhibitors may be obtained by targeting a secondary aryl phosphate-binding site as well as the catalytic site. We report here the crystal structures of PTP1B in complex with first and second generation aryldifluoromethyl-phosphonic acid inhibitors. While all compounds bind in a previously unexploited binding pocket near the primary binding site, the second generation compounds also reach into the secondary binding site, and exhibit moderate selectivity for PTP1B over the closely related T-cell phosphatase. The molecular basis for the selectivity has been confirmed by single point mutation at position 52, where the two phosphatases differ by a phenylalanine-to-tyrosine switch. These compounds present a novel platform for the development of potent and selective PTP1B inhibitors.

is also an important source of several metabolic signals. As an integral part of the glycerolipid/fatty acid cycle ( 1 ), lipolysis produces lipid signals that modify cellular functions such as glucose-stimulated insulin secretion ( 2 ) and metabolic pathways and also alter transcription of various genes ( 1, 3 ). TG breakdown to glycerol and fatty acids is accomplished by the sequential action of adipose triglyceride lipase (ATGL), which hydrolyzes TG to 2,3-or 1,3-diacylglycerol (DAG), followed by hormone sensitive lipase (HSL)-mediated DAG hydrolysis to generate 1-or 2-monoacylglycerol (MAG) ( 1, 3 ). Finally MAG is hydrolyzed by either the classical MAG lipase (MAGL) or the recently described ␣ / ␤ -hydrolase domain 6 (ABHD6) to glycerol and FFA ( 4-6 ). Receptor-mediated signaling at the plasma membrane leads to the phospholipase-C-dependent formation of 1,2-DAG, which is further hydrolyzed by sn -1-DAG lipases (DAGL) ␣ or ␤ ( 7 ), to form mostly 2-MAG.Recent studies indicated the physiological importance of many of these lipases. Thus, ATGL has been implicated in lipid homeostasis in adipocytes, myocardium and skeletal muscle, cancer cachexia ( 1,3,8 ), and the regulation of insulin secretion in pancreatic ␤ -cells ( 9 ). HSL was shown to be important in adipose lipid metabolism ( 10 ) and in the regulation of glucose-stimulated insulin secretion ( 11,12 ). MAGL, which hydrolyzes the endocannabinoid Abstract Lipids are used as cellular building blocks and condensed energy stores and also act as signaling molecules. The glycerolipid/ fatty acid cycle, encompassing lipolysis and lipogenesis, generates many lipid signals. Reliable procedures are not available for measuring activities of several lipolytic enzymes for the purposes of drug screening, and this resulted in questionable selectivity of various known lipase inhibitors. We now describe simple assays for lipolytic enzymes, including adipose triglyceride lipase (ATGL), hormone sensitive lipase (HSL), sn -1-diacylglycerol lipase (DAGL), monoacylglycerol lipase, ␣ / ␤ -hydrolase domain 6, and carboxylesterase 1 (CES1) using recombinant human and mouse enzymes either in cell extracts or using purifi ed enzymes. We observed that many of the reported inhibitors lack specifi city. Thus, Cay10499 (HSL inhibitor) and RHC20867 (DAGL inhibitor) also inhibit other lipases. Marked differences in the inhibitor sensitivities of human ATGL and HSL compared with the corresponding mouse enzymes was noticed. Thus, ATGListatin inhibited mouse ATGL but not human ATGL, and the HSL inhibitors WWL11 and Compound 13f were effective against mouse enzyme but much less potent against human enzyme. Many of these lipase inhibitors also inhibited human CES1. Results describe reliable assays for measuring lipase activities that are amenable for drug screening and also caution about the specifi city of the many earlier described lipase inhibitors.