Nickel chelation therapy as an approach to combat multi-drug resistant enteric pathogens

Stéphane L Benoit,Robert J Maier,Alan A Schmalstig,John Glushka,Susan E Maier,Arthur S Edison

doi:10.1038/s41598-019-50027-0

Stéphane L Benoit, Robert J Maier + Show 4 more

Open Access

https://doi.org/10.1038/s41598-019-50027-0

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Abstract

The nickel (Ni)-specific chelator dimethylglyoxime (DMG) has been used for many years to detect, quantitate or decrease Ni levels in various environments. Addition of DMG at millimolar levels has a bacteriostatic effect on some enteric pathogens, including multidrug resistant (MDR) strains of Salmonella Typhimurium and Klebsiella pneumoniae. DMG inhibited activity of two Ni-containing enzymes, Salmonella hydrogenase and Klebsiella urease. Oral delivery of nontoxic levels of DMG to mice previously inoculated with S. Typhimurium led to a 50% survival rate, while 100% of infected mice in the no-DMG control group succumbed to salmonellosis. Pathogen colonization numbers from livers and spleens of mice were 10- fold reduced by DMG treatment of the Salmonella-infected mice. Using Nuclear Magnetic Resonance, we were able to detect DMG in the livers of DMG-(orally) treated mice. Inoculation of Galleria mellonella (wax moth) larvae with DMG prior to injection of either MDR K. pneumoniae or MDR S. Typhimurium led to 40% and 60% survival, respectively, compared to 100% mortality of larvae infected with either pathogen, but without prior DMG administration. Our results suggest that DMG-mediated Ni-chelation could provide a novel approach to combat enteric pathogens, including recalcitrant multi-drug resistant strains.

Highlights

The nickel (Ni)-specific chelator dimethylglyoxime (DMG) has been used for many years to detect, quantitate or decrease Ni levels in various environments
A recent study conducted over 3 years in a French hospital found that bloodstream infections with multidrug resistant (MDR) Enterobacteriaceae accounted for more than 70% of all bloodstream infections with MDR bacterial strains[2]
The inhibitory effect of DMG on bacterial growth was tested on three strains: MDR K. pneumoniae (ATCC BAA2472), MDR S

Summary

Results and Discussion

The nickel-specific chelator DMG inhibits growth of various enterobacteriaceae. The inhibitory effect of DMG on bacterial growth was tested on three strains: MDR K. pneumoniae (ATCC BAA2472), MDR S. To study the effect of Ni-chelation on urease activity in MDR K. pneumoniae BAA-2472, cells were grown overnight in LB broth supplemented with sublethal concentrations of DMG (no apparent growth inhibition was observed under any of the DMG concentrations), harvested and broken, and urease assays were performed on cell-free extracts (Table 2). Typhimurium is reproducible, typically resulting in a 100% mortality rate within a week[11,12,13] This was confirmed : oral infection of mice with 106 bacterial cells (and no DMG) led to 100% mortality within 6 days in three independent experiments (Fig. 3 and data not shown, N = 12 total).

End treatment

DMG only

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