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Biomedical subjects

John J Barker

Publications and source records attributed to John J Barker.

2 recordsLinked to original sources

Antibacterial drug discovery and structure-based design.

Bacterial resistance continues to develop and pose a significant threat, both in hospitals and, more recently, in the community. A focus on other therapeutic areas by the larger pharmaceutical companies has left a shortfall in the pipeline of novel antibacterials. Recently, many new structures have been studied by structure-genomics initiatives, delivering a wealth of targets to consider. Using the tools of structure-based design, antibacterial discovery must exploit these targets to accelerate the process of drug discovery.

Acetamides↗

Inhibitors of phosphopantetheine adenylyltransferase.

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.

Coenzyme A↗