Abstract
Pyrithione (2-mercaptopyridine-N-oxide) is a metal binding modified pyridine, the antibacterial activity of which was described over 60 years ago. The formulation of zinc-pyrithione is commonly used in the topical treatment of certain dermatological conditions. However, the characterisation of the cellular uptake of pyrithione has not been elucidated, although an unsubstantiated assumption has persisted that pyrithione and/or its metal complexes undergo a passive diffusion through cell membranes. Here, we have profiled specific membrane transporters from an unbiased interrogation of 532 E. coli strains of knockouts of genes encoding membrane proteins from the Keio collection. Two membrane transporters, FepC and MetQ, seemed involved in the uptake of pyrithione and its cognate metal complexes with copper, iron, and zinc. Additionally, the phenotypes displayed by CopA and ZntA knockouts suggested that these two metal effluxers drive the extrusion from the bacterial cell of potentially toxic levels of copper, and perhaps zinc, which hyperaccumulate as a function of pyrithione. The involvement of these distinct membrane transporters contributes to the understanding of the mechanisms of action of pyrithione specifically and highlights, more generally, the important role that membrane transporters play in facilitating the uptake of drugs, including metal–drug compounds.
Highlights
One strategy to combat this mechanism of drug resistance could be to provide a substance that is not itself antibacterial in the absence of any β-lactamase activity but becomes so in its presence
Using genetically modified strains of the Gram-negative E. coli, we have presented here a discrete number of membrane transporters likely involved in the facilitated transit in and out of the cell of pyrithione and its associated metal cations, most relevantly Cu and Zn
The properties of pyrithione as a metal ionophore are necessary for its cytotoxicity, as originally reported [59], at concentrations similar to those reported here for E. coli, in the presence of added Cu (Table 3 and Figure 7, WT strain)
Summary
One strategy to combat this mechanism of drug resistance could be to provide a substance that is not itself antibacterial in the absence of any β-lactamase activity but becomes so in its presence. Noting that copper compounds can be significantly antibacterial [27,28,29,30,31,32,33], an embodiment of this strategy was recently proposed that exploited the ability of β-lactamases to activate a prochelator compound (PcephPT, phenylacetamido-cephem-pyrithione) to selectively release pyrithione (2-mercaptopyridine N-oxide) and thereby facilitate its known copper-dependent cytotoxicity [34,35]. We found that the combination of Cu(II) and pyrithione was highly bacteriotoxic This toxicity was manifested by the addition of PcephPT only in strains expressing μ-lactamase activity that became tolerant to pyrithione and
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