Amikacin potentiator activity of zinc complexed to a pyrithione derivative with enhanced solubility

Abstract

Resistance to amikacin in Gram-negatives is usually mediated by the 6'-N-acetyltransferase type Ib [AAC(6')-Ib], which catalyzes the transfer of an acetyl group from acetyl CoA to the 6' position of the antibiotic molecule. A path to continue the effective use of amikacin against resistant infections is to combine it with inhibitors of the inactivating reaction. We have recently observed that addition of Zn2+ to in-vitro enzymatic reactions, obliterates acetylation of the acceptor antibiotic. Furthermore, when added to amikacin-containing culture medium in complex to ionophores such as pyrithione (ZnPT), it prevents the growth of resistant strains. An undesired property of ZnPT is its poor water-solubility, a problem that currently affects a large percentage of newly designed drugs. Water-solubility helps drugs to dissolve in body fluids and be transported to the target location. We tested a pyrithione derivative described previously (Magda et al. Cancer Res 68:5318–5325, 2008) that contains the amphoteric group di(ethyleneglycol)-methyl ether at position 5 (compound 5002), a modification that enhances the solubility. Compound 5002 in complex with zinc (Zn5002) was tested to assess growth inhibition of amikacin-resistant Acinetobacter baumannii and Klebsiella pneumoniae strains in the presence of the antibiotic. Zn5002 complexes in combination with amikacin at different concentrations completely inhibited growth of the tested strains. However, the concentrations needed to achieve growth inhibition were higher than those required to achieve the same results using ZnPT. Time-kill assays showed that the effect of the combination amikacin/Zn5002 was bactericidal. These results indicate that derivatives of pyrithione with enhanced water-solubility, a property that would make them drugs with better bioavailability and absorption, are a viable option for designing inhibitors of the resistance to amikacin mediated by AAC(6')-Ib, an enzyme commonly found in the clinics.

Interactions of Antibacterial Antibiotics with Magnesium and Zinc

“…The presence in the culture medium of an ionophore for zinc such as pyrithione (ZnPT) determines the reduction of the growth of some resistant strains of A.baumani and K.pneumoniae. An ionophore more water soluble than ZnPT such as compound 5002 which forms complexes with zinc added in the incubation medium in association with amikacin completely inhibits the growth of these two resistant bacteria [23] .…”

Restoring susceptibility to aminoglycosides: identifying small molecule inhibitors of enzymatic inactivation

“…93,94 In the cases of Cu 2+ and Zn 2+ , the concentrations required to observe a phenotypic conversion to susceptibility were significantly reduced when coordination complexes of the cations and ionophores were added to the culture medium. [94][95][96][97][98][99] The mechanism of inhibition of resistance remains to be understood. However, an attractive hypothesis is that the antibiotic in complex with the metal ion becomes a poor substrate.…”