Restoration of susceptibility to amikacin by 8-hydroxyquinoline analogs complexed to zinc

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 Zn 2+ 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 Zn 2+ 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 Zn 2+ and amikacin was bactericidal. Addition of 8-hydroxyquinoline, clioquinol, or 5,7-diiodo-8-hydroxyquinoline, alone or in combination with Zn 2+ , and amikacin to HEK293 cells did not result in significant toxicity. These results indicate that ionophores in complex with Zn 2+ 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.

Aminoglycoside 6′-N-acetyltransferase Type Ib [AAC(6′)-Ib]-Mediated Aminoglycoside Resistance: Phenotypic Conversion to Susceptibility by Silver Ions

“…In the case of the AAC(6 )-Ib, the most common aminoglycoside resistance enzyme among AAC(6 )-I-carrying Gram-negatives [21,32], some small molecules have been identified that act as enzymatic inhibitors [20,23,29,[33][34][35]. In addition to these advances, recent research revealed that Zn 2+ and other metal ions inhibit the acetylation of aminoglycosides mediated by AAC(6 )-Ib in vitro [25][26][27][28]36,37]. The mechanism by which these metal ions interfere with enzymatic acetylation of aminoglycosides mediated by AAC(6 )-Ib is not yet known.…”

“…This path proved to be successful in the case of β-lactamase-mediated resistance to β-lactams [22,24]. The recent finding that metal ions such as Zn 2+ and Cu 2+ , in complex with ionophores, inhibit the acetylation of aminoglycosides mediated by AAC(6 )-Ib and reverse amikacin resistance in laboratory assays increased the expectations that viable formulations that can treat infections caused by resistant A. baumannii will be designed in the near future [25][26][27][28]. In this article, we describe the inhibition of AAC(6 )-Ib-mediated amikacin-resistance by Ag 1+ in A. baumannii and E. coli.…”

A Novel Calcium-Activated Potassium Channel Controls Membrane Potential and Intracellular pH in Trypanosoma cruzi

“…Barium has been described as a potent modulator with activation and blockage effects depending on cell and channel types (Inomoto and Tokimasa, 1998;Zhou et al, 2012;Wrighton et al, 2015;Kourghi et al, 2017), but its lack of selectivity precludes its use as a potential therapeutic drug. Recently, it has been shown that combination of antibiotics with zinc restore the susceptibility of antibiotic resistant Gram (-) bacteria (Magallon et al, 2019). This approach is worth of consideration, as the combination of anti-parasitic drugs of low efficacy with barium or other less toxic metals could increase the susceptibility of the parasites and provide new avenues for drug development.…”

Virtual screening and molecular dynamics study of approved drugs as inhibitors of spike protein S1 domain and ACE2 interaction in SARS-CoV-2

“…Amikacin: Amikacin is an antibiotic of aminoglycoside class [ 55 ]. In our study amikacin showed interaction with Tyr495, tyr453, arg403, lys417 and glu406 residues of RBD region.…”