Designing an Inhibitor for Aac(6')-II : Fragment-based Drug Design using SAR by NMR

Aminoglycosides are valuable broad-spectrum antibiotics effective in both Gram-positive and Gram-negative bacteria. Antibiotic resistance has however been a scourge since the advent of modern antibiotics. One of the main mechanisms of resistance to aminoglycosides is antibiotic modification by the clinically widespread enzyme aminoglycoside N-6'-acetyltransferase. Inhibiting resistance-causing enzymes is an important strategy among the multiple approaches to counter antibiotic resistance. The Auclair lab has previously developed a series of aminoglycoside-coenzyme A bisubstrates that was found to be potent inhibitors of AAC(6')-Ii, but lacked activity in cell-based assays. In order to combat aminoglycoside resistance, this book aims at developing a new class of AAC(6') inhibitors using fragment-based drug design with NMR-based assays for the initial screening. This approach has the advantage of potentially identifying new structural scaffolds that are fundamentally different from those that have been previously developed in the group.