ABSTRACT
Phosphopantetheine adenylyltransferase (PPAT) is an essential enzyme in Coenzyme A biosynthesis. Because bacterial PPAT and mammalian PPAT are dissimilar, this enzyme is an attractive antibacterial target. Based on the structure of the substrate, 4-phosphopantetheine, a dipeptide library was designed, synthesised and tested against Escherichia coli PPAT. The most potent inhibitor PTX040334 was co-crystallised with E. coli PPAT. With this structural information, a rational iterative medicinal chemistry program was initiated, aimed at increasing the number of inhibitor-enzyme interactions. A very potent and specific inhibitor, PTX042695, with an IC(50) of 6 nM against E.coli PPAT, but with no activity against porcine PPAT, was obtained.
Subject(s)
Dipeptides/pharmacology , Enzyme Inhibitors/pharmacology , Nucleotidyltransferases/antagonists & inhibitors , Coenzyme A/biosynthesis , Dipeptides/chemical synthesis , Dipeptides/chemistry , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Escherichia coli/drug effects , Escherichia coli/enzymology , Inhibitory Concentration 50 , Models, Chemical , Models, Molecular , Nucleotidyltransferases/metabolismABSTRACT
The urgent need for new antibiotics has led to an explosion in the number and diversity of antibiotic drug targets under investigation. The majority of such targets are enzymes required for essential cellular functions. Often, such novel targets are completely unexploited for antibiotic therapy and therefore have the advantage of avoiding current resistance mechanisms. In general, the most advanced novel targets are drawn from processes where an existing antibacterial compound has validated that process for antibiotic therapy. This review describes a number of the more promising targets under development.
