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

What was studied

Nickel chelation therapy was investigated as a strategy to inhibit multidrug-resistant (MDR) enteric pathogens, with a focus on how dimethylglyoxime (DMG) affects the growth and virulence of Salmonella enterica serovar Typhimurium and Klebsiella pneumoniae. This work explored how nickel sequestration disrupts key microbial enzymes—particularly hydrogenases and urease—central to the metabolic fitness and pathogenicity of these organisms. Since nickel-dependent enzymes form well-established components of microbial physiology, these findings also contribute a microbiome-relevant signature: the dependency of certain pathogens on nickel for enzymatic activity. The study provides a detailed look at how DMG interferes with these microbial systems.

Who was studied

The investigation used three bacterial strains: MDR Salmonella Typhimurium ATCC 700408, non-MDR Salmonella Typhimurium ATCC 14028, and MDR Klebsiella pneumoniae ATCC BAA-2472. In vivo analysis involved BALB/c mice and Galleria mellonella larvae to assess toxicity and therapeutic potential. These models allowed evaluation of systemic and localised effects of DMG, including pathogen load in organs and host survival outcomes.

Most important findings

DMG displayed bacteriostatic effects against all tested Enterobacteriaceae strains at millimolar concentrations, with growth suppression thresholds differing by species. Hydrogenase activity in Salmonella—an enzyme system heavily reliant on nickel—was significantly inhibited by DMG beginning at 0.5 mM, and nearly abolished at 10 mM. The table on page 3 of the article clearly shows dose-dependent inhibition, with activity restored partially by the addition of nickel chloride. The page 4 urease activity table illustrates similar findings for Klebsiella, showing complete loss of urease function at 5 mM DMG. These enzymatic disruptions align with known microbial metabolic pathways that depend on nickel cofactors. In mouse models, oral DMG significantly reduced Salmonella organ burden by approximately one log and improved survival up to 50%. In wax moth larvae, pretreatment with DMG improved survival from 0% to 40–60% when challenged with MDR organisms. DMG itself showed no meaningful toxicity in either model across a wide dosing range. NMR analysis confirmed detectable levels of DMG in mouse liver tissue, supporting systemic absorption and explaining reductions in microbial virulence.

Key implications

The findings indicate that nickel chelation represents a promising avenue for targeting MDR pathogens that depend on nickel-requiring enzymes for survival and virulence. For microbiome-focused clinical applications, the study expands a potentially valuable signature: the reliance of certain pathogens on nickel-dependent metabolic pathways. Inhibitors like DMG may offer adjunctive therapeutic strategies in cases where antibiotic resistance limits treatment options. Moreover, identifying nickel-dependent pathways broadens the landscape for precision microbiome manipulation by exploiting metal-based vulnerabilities in pathogenic organisms while minimally affecting the host. Further studies would be required to validate safety, organ distribution, and clinical efficacy in humans.

Citation

Benoit SL, Schmalstig AA, Glushka J, Maier SE, Edison AS, Maier RJ. Nickel chelation therapy as an approach to combat multi-drug resistant enteric pathogens.Scientific Reports. 2019;9:13851. doi:10.1038/s41598-019-50027-0