Plazomicin Retains Antibiotic Activity against Most Aminoglycoside Modifying Enzymes

Plazomicin is a next-generation, semisynthetic aminoglycoside antibiotic currently under development for the treatment of infections due to multidrug-resistant <i>Enterobacteriaceae</i>. The compound was designed by chemical modification of the natural product sisomicin to provide protection from common aminoglycoside modifying enzymes that chemically alter these drugs via <i>N</i>-acetylation, <i>O</i>-adenylylation, or <i>O</i>-phosphorylation. In this study, plazomicin was profiled against a panel of isogenic strains of <i>Escherichia coli</i> individually expressing twenty-one aminoglycoside resistance enzymes. Plazomicin retained antibacterial activity against 15 of the 17 modifying enzyme-expressing strains tested. Expression of only two of the modifying enzymes, <i>aac­(2′)-Ia</i> and <i>aph­(2″)-IVa,</i> decreased plazomicin potency. On the other hand, expression of 16S rRNA ribosomal methyltransferases results in a complete lack of plazomicin potency. <i>In vitro</i> enzymatic assessment confirmed that AAC(2′)-Ia and APH(2′′)-IVa (aminoglycoside acetyltransferase, AAC; aminoglycoside phosphotransferase, APH) were able to utilize plazomicin as a substrate. AAC(2′)-Ia and APH(2′′)-IVa are limited in their distribution to <i>Providencia stuartii</i> and Enterococci, respectively. These data demonstrate that plazomicin is not modified by a broad spectrum of common aminoglycoside modifying enzymes including those commonly found in <i>Enterobacteriaceae</i>. However, plazomicin is inactive in the presence of 16S rRNA ribosomal methyltransferases, which should be monitored in future surveillance programs