Abstract
Gram-negative pathogens resistant to amikacin and other aminoglycosides of clinical relevance usually harbor the 6’-N-acetyltransferase type Ib [AAC(6')-Ib], an enzyme that catalyzes inactivation of the antibiotic by acetylation using acetyl-CoA as donor substrate. Inhibition of the acetylating reaction could be a way to induce phenotypic conversion to susceptibility in these bacteria. We have previously observed that Zn2+ acts as an inhibitor of the enzymatic acetylation of aminoglycosides by AAC(6')-Ib, and in complex with ionophores it effectively reduced the levels of resistance in cellulo. We compared the activity of 8-hydroxyquinoline, three halogenated derivatives, and 5-[N-Methyl-N-Propargylaminomethyl]-8-Hydroxyquinoline in complex with Zn2+ to inhibit growth of amikacin-resistant Acinetobacter baumannii in the presence of the antibiotic. Two of the compounds, clioquinol (5-chloro-7-iodo-8-hydroxyquinoline) and 5,7-diiodo-8-hydroxyquinoline, showed robust inhibition of growth of the two A. baumannii clinical isolates that produce AAC(6')-Ib. However, none of the combinations had any activity on another amikacin-resistant A. baumannii strain that possesses a different, still unknown mechanism of resistance. Time-kill assays showed that the combination of clioquinol or 5,7-diiodo-8-hydroxyquinoline with Zn2+ and amikacin was bactericidal. Addition of 8-hydroxyquinoline, clioquinol, or 5,7-diiodo-8-hydroxyquinoline, alone or in combination with Zn2+, and amikacin to HEK293 cells did not result in significant toxicity. These results indicate that ionophores in complex with Zn2+ could be developed into potent adjuvants to be used in combination with aminoglycosides to treat Gram-negative pathogens in which resistance is mediated by AAC(6')-Ib and most probably other related aminoglycoside modifying enzymes.
Highlights
Among many mechanisms bacteria have evolved to resist antibiotics, enzymatic modification is one of the most efficient [1]
We recently showed that two classes of ionophores, clioquinol (5-chloro-7-iodo-8-hydroxyquinoline)(CI8HQ) and pyrithione (Nhydroxypyridine-2-thione), when complexed to Zn2+ or Cu2+, significantly reduce the levels of resistance to amikacin in Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii strains harboring the aac(6')-Ib gene [24,25,26]
We have recently found that ionophores complexed to Zn2+ or Cu2+ could be potentiators that decrease the levels of resistance to amikacin in K. pneumoniae and A. baumannii clinical isolates [23,24,25]
Summary
Among many mechanisms bacteria have evolved to resist antibiotics, enzymatic modification is one of the most efficient [1]. One way to overcome this problem is the design of new antimicrobials such as the recent introduction of plazomicin [7] Since this is a slow and expensive process and resistance will inevitably develop against the new antibiotics, these efforts must be complemented by other strategies to prolong the useful life of existing drugs [1, 2, 8,9,10,11]. The ongoing studies and uses of these compounds indicate that human toxicity is not a serious impediment in their development as drugs for diverse diseases [29, 31] These facts make CI8HQ and other substituted 8-hydroxyquinolines excellent candidates to be used in combination with aminoglycosides in the treatment of resistant infections. We compared the effect of commercially available substituted 8-hydroxyquinolines complexed to Zn2+ on growth of amikacin-resistant A. baumannii clinical isolates
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