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

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.

The nickel-chelator dimethylglyoxime inhibits human amyloid beta peptide in vitro aggregation

“…Hence it is preferable to use chelators with select affinity towards non-essential metals: the Ni-specific chelator DMG is therefore a good candidate. Indeed, DMG has been used for many years to detect, quantitate or decrease Ni levels in various environments; it can also be used to inhibit the growth of bacteria, including multidrug resistant Enterobacteriaceae, as recently demonstrated by our group 55 . Mammalian hosts do not contain known Ni-dependent enzymes, which makes Ni-chelation therapy an attractive approach 47 .…”

“…NMR was successfully used to detect DMG in the livers of mice subjected to daily oral doses (6. 1 mg) of aqueous DMG for 3 days 55 . In the present study, the same treatment was administered ( e.g.…”

“…On the other hand, most bacteria, including pathogenic ones, require nickel as cofactor for one or several enzymes, such as [Ni–Fe] hydrogenase(s) 61 or urease 47 . Thus, DMG-mediated inhibition of these enzymes, as demonstrated with Salmonella Typhimurium hydrogenases or Klebsiella pneumoniae urease, leads to bacterial growth inhibition, both in the mouse and in the wax moth animal models 55 . In the present study, we showed that DMG can drastically reduce, and even abolish A β 40 peptide aggregation.…”

“…Upon thawing, brains were cut into pieces and homogenized in 2 mL sterile deionized water, incubated for 1 h at 90 °C, sonicated for 20 s and spun down (16,800 × g for 6 min). Supernatants were passaged through a 0.45 μm filter unit and analyzed by FTICR-MS (see above) and Nuclear Magnetic Resonance (NMR), as previously described 55 .…”

Identifying virulence determinants of multidrug-resistant Klebsiella pneumoniae in Galleria mellonella

“…Fitness factors required for intestinal colonisation of mice have also been examined in an ST258 background (Benoit et al . 2019), although this screen was not comprehensive due to various experimental factors.…”