Zinc exposure increases resistance to polymyxins in Pseudomonas aeruginosa through activation of the arn operon and two-component regulatory systems
Metal cations have long been known to play a role in driving antibiotic resistance. The metal cation Zn2+ has previously been shown to drive antibiotic resistance in various bacterial species, including the opportunistic pathogen Pseudomonas aeruginosa, but never to polymyxins. Here, we have investigated the effect of ZnCl2 on polymyxin resistance in P. aeruginosa. Weeklong exposure to 2 mM ZnCl2 elicited thousand-fold increases in polymyxin resistance frequency in P. aeruginosa wild type lab strain K767 and clinical strain K2153, but not wild type lab strain PA14; this effect is Zn-specific and could not be reproduced with MgCl2. Additionally, this effect appears to be specific to P. aeruginosa, as Zn-driven polymyxin resistance could not be elicited in Stenotrophomonas maltophilia strain K1199, nor Escherichia coli strain K193 and K155. However, ZnCl2-exposed polymyxin-resistant strains did not show increased tolerance to growth in 2mM ZnCl2. Using knockout strains, the two-component regulatory systems ColRS, PmrAB, and ParRS were found to be necessary for the increase in polymyxin resistance frequency to occur in response to ZnCl2; the arnBCADTEF operon which controls polymyxin resistance is also necessary. arnB was found to be upregulated 2 to 3-fold in several of the ZnCl2-exposed, polymyxin-resistant mutant strains. As well, those strains where arnB was upregulated also harboured a parR point mutation, suggesting this mutation may be responsible for polymyxin resistance. Using a parR knockout strain, ParR was found to be necessary for the upregulation of arnB by Zn. Overall, these data suggest that ZnCl2 plays an important role in driving polymyxin resistance in P. aeruginosa.
URI for this recordhttp://hdl.handle.net/1974/25666
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