Turning an aminoglycoside resistance problem into a solution

Abstract:

Aminoglycosides are broad-spectrum antibiotics commonly used for the treatment of serious bacterial infections. Over six decades of intensive clinical use of aminoglycosides has led to the emergence of bacterial resistance to this family of drugs. A highly prevalent mode of bacterial resistance to aminoglycosides evolved through the acquisition of enzymes that modify the antibiotics. These perform three chemical alterations of the drug: N-acetylation by acetyltransferases (AACs), adenylation by adenyltransferases (ANTs), or phosphorylation by phosphotransferases (APHs). We are taking advantage of the substrate and cosubstrate promiscuity of AACs (AAC(3)-IV and AAC(6’)-APH(2”)) to generate novel N-acylated aminoglycoside antibiotics.