SILVER MEDIATED PHENOTYPIC SUSCEPTIBILITY CONVERSION OF AMINOGLYCOSIDE RESISTANT STRAINS HARBORING AAC(6')-Ib

The rise of multidrug resistant Gram-negative and Gram-positive bacteria may represent the most serious threat to human health. Decades of medical advancements are jeopardized by increased numbers of isolated clinical strains demonstrating acquired resistances to multiple classes of antibiotics. Aminoglycosides represent an effective class of antibiotics for use against pathogenic Gram-negative infections, though the increasing prevalence of modifying enzymes is putting their efficacy at risk. The enzyme 6′-N-acetyltransferase type Ib [AAC(6′)-Ib] is ubiquitously found in strains of resistant Acinetobacter and inactivates aminoglycosides by catalyzing acetylation of the 6’-carbon amine, utilizing acetyl-CoA as a donor substrate. The aac(6’)-Ib gene has been observed in the chromosomal DNA and integrons of Gram-negative bacteria as well as in mobile genetic elements such as transposons and plasmids, suggesting the dissemination of this and other resistant genes as an inevitable threat to human health. In the case of resistant bacteria, therapies combining an aminoglycoside with ionophore-complexed metal ions has shown the ability to restore antimicrobial susceptibility of resistant strains of bacteria. For this research silver (Ag1+) was evaluated for its potential efficacy as a target inhibitor to the enzymatic aminoglycoside inactivation by AAC(6’)-Ib. Results demonstrate that silver (Ag1+), in combination with aminoglycosides, displayed substantial inhibition to antibiotic resistance inferred by AAC(6’)-Ib when used in concentrations below 10 µM. Additionally, combinatory trials exhibited restored aminoglycoside susceptibility and bactericidal outcomes, independent of toxicity, in strains of Acinetobacter baumannii and Escherichia coli harboring aac(6’)-Ib mediated resistance