Abstract
Clinical resistance to amikacin and other aminoglycosides is usually due to the enzymatic acetylation of the antimicrobial molecule. A ubiquitous resistance enzyme among Gram-negatives is the aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6′)-Ib], which catalyzes acetylation using acetyl-CoA as a donor substrate. Therapies that combine the antibiotic and an inhibitor of the inactivation reaction could be an alternative to treat infections caused by resistant bacteria. We previously observed that metal ions such as Zn2+ or Cu2+ in complex with ionophores interfere with the AAC(6′)-Ib-mediated inactivation of aminoglycosides and reduced resistance to susceptibility levels. Ag1+ recently attracted attention as a potentiator of aminoglycosides′ action by mechanisms still in discussion. We found that silver acetate is also a robust inhibitor of the enzymatic acetylation mediated by AAC(6′)-Ib in vitro. This action seems to be independent of other mechanisms, like increased production of reactive oxygen species and enhanced membrane permeability, proposed to explain the potentiation of the antibiotic effect by silver ions. The addition of this compound to aac(6′)-Ib harboring Acinetobacter baumannii and Escherichia coli cultures resulted in a dramatic reduction of the resistance levels. Time-kill assays showed that the combination of silver acetate and amikacin was bactericidal and exhibited low cytotoxicity to HEK293 cells.
Highlights
Silver has been used for the treatment of human diseases since ancient times [1,2]
Our experiments showed that concentrations lower than 10 μM of silver acetate completely abolish resistance to amikacin in aac(6 )Ib-carrying A. baumannii and E. coli strains
The potentiating effect of Ag1+ ions on aminoglycoside antibiotics has been recently reported [4,7]. One of these reports proposed that an increase in reactive oxygen species production is the primary mechanism by which silver ions act as adjuvants [4]. Another series of experiments pointed to an enhanced uptake level of antibiotics induced by silver ions as the molecular mechanism behind the observed activity [7]
Summary
Until the advent of antibiotics in the mid-20th century, silver may have been the most used medicine to treat infections [2]. Acinetobacter baumannii is responsible for a large fraction of multiresistant hospital outbreaks [10,11]. Infections caused by this bacterium present multiple clinical manifestations, high mortality, and refraction to treatment [12,13,14]. These characteristics positioned A. baumannii within the U.S Centers for Disease Control s list of threats to human health [15,16].
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