Inhibitors of Aminoglycoside Resistance Activated in Cells

The most common mechanism of resistance to aminoglycoside antibiotics entails bacterial expression of drug-metabolizing enzymes, such as the clinically widespread aminoglycoside <i>N</i>-6′-acetyltransferase (AAC­(6′)). Aminoglycoside-CoA bisubstrates are highly potent AAC(6′) inhibitors; however, their inability to penetrate cells precludes <i>in vivo</i> studies. Some truncated bisubstrates are known to cross cell membranes, yet their activities against AAC(6′) are in the micromolar range at best. We report here the synthesis and biological activity of aminoglycoside-pantetheine derivatives that, although devoid of AAC(6′) inhibitory activity, can potentiate the antibacterial activity of kanamycin A against an aminoglycoside-resistant strain of <i>Enterococcus faecium</i>. Biological studies demonstrate that these molecules are potentially extended to their corresponding full-length bisubstrates by enzymes of the coenzyme A biosynthetic pathway. This work provides a proof-of-concept for the utility of prodrug compounds activated by enzymes of the coenzyme A biosynthetic pathway, to resensitize resistant strains of bacteria to aminoglycoside antibiotics