INHIBITION OF AAC(2')-IA MEDIATED PLAZOMICIN RESISTANCE BY SILVER IONS

Repeated use of antibiotics has led to widespread dissemination of resistance. One example of combating resistance is to create new antibiotics. Plazomicin is an aminoglycoside that received FDA approval in 2018. Plazomicin is impervious to most aminoglycoside-modifying enzymes (AMEs), including Aminoglyoside 6’-N-Acetyltransferase subtype Ib (AAC(6’)-Ib), one of the most prevalent AMEs, notable for its ability to deactivate amikacin, which is also impervious to most AMEs. However, plazomicin is vulnerable to Aminoglyoside 2’-N-Acetyltransferase subtype Ia (AAC(2’)-Ia). The Tolmasky lab has previously used metal cations, including Zn2+, Cu2+, and Ag+, to inhibit AAC(6’)-Ib-mediated aminoglycoside resistance. I tested these metal cations to see if their properties could be replicated against AAC(2’)-Ia. Ag+ was shown to inhibit AAC(2’)-Ia-mediated plazomicin resistance. Enzymatic activity assays showed silver-inhibited plazomicin acetylation by AAC(2’)-Ia. Growth inhibition assays showed silver-restored susceptibility to plazomicin. Time-kill assays showed the cocktail was bactericidal, and cytotoxicity assays showed it was selectively toxic. Future studies will examine animal models to see if this cocktail increases the survivability of infections hosting AAC(2’)-Ia. Given silver was able to inhibit aminoglycoside acetylation from two different AAC enzymes, we can also explore if silver can protect against other AACs and even other AMEs.