Inhibitors of Aminoglycoside Resistance Activated in Cells

The most common mechanism of resistance toaminoglycoside antibiotics entails bacterial expression of drugmetabolizingenzymes, such as the clinically widespread aminoglycosideN-6′-acetyltransferase (AAC(6′)). Aminoglycoside-CoA bisubstratesare highly potent AAC(6′) inhibitors; however, their inability topenetrate cells precludes in vivo studies. Some truncated bisubstratesare known to cross cell membranes, yet their activities against AAC(6′)are in the micromolar range at best. We report here the synthesis andbiological activity of aminoglycoside-pantetheine derivatives that,although devoid of AAC(6′) inhibitory activity, can potentiate theantibacterial activity of kanamycin A against an aminoglycosideresistantstrain of Enterococcus faecium. Biological studies demonstrate that these molecules are potentially extended to theircorresponding full-length bisubstrates by enzymes of the coenzyme A biosynthetic pathway. This work provides a proof-ofconceptfor the utility of prodrug compounds activated by enzymes of the coenzyme A biosynthetic pathway, to resensitizeresistant strains of bacteria to aminoglycoside antibiotics