Nickel chelation therapy as an approach to combat multi-drug resistant enteric pathogens Original paper
Researched by:
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Karen Pendergrass
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Karen Pendergrass
Karen Pendergrass is a microbiome researcher specializing in microbiome-targeted interventions (MBTIs). She systematically analyzes scientific literature to identify microbial patterns, develop hypotheses, and validate interventions. As the founder of the Microbiome Signatures Database, she bridges microbiome research with clinical practice. In 2012, based on her own investigative research, she became the first documented case of FMT for Celiac Disease—four years before the first published case study.
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Metals
Metals
OverviewHeavy metals play a significant and multifaceted role in the pathogenicity of microbial species. Their involvement can be viewed from two primary perspectives: the toxicity of heavy metals to microbes and the exploitation of heavy metals by microbial pathogens to establish infections and evade the host immune response. Understanding these aspects is critical for both […]
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Karen Pendergrass
Researched by:
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Karen Pendergrass
ID
Karen Pendergrass
Microbiome Signatures identifies and validates condition-specific microbiome shifts and interventions to accelerate clinical translation. Our multidisciplinary team supports clinicians, researchers, and innovators in turning microbiome science into actionable medicine.
Karen Pendergrass
What was studied?
This experimental study investigated the therapeutic potential of the nickel-specific chelator dimethylglyoxime (DMG) as an antimicrobial intervention against multidrug-resistant (MDR) enteric pathogens, specifically Salmonella enterica serovar Typhimurium and Klebsiella pneumoniae. The research assessed whether nickel chelation by DMG could inhibit the growth and virulence of these pathogens in vitro and in vivo through interference with essential Ni-dependent bacterial enzymes.
Who was studied?
The study utilized bacterial strains of MDR Klebsiella pneumoniae (ATCC BAA-2472) and MDR Salmonella Typhimurium (ATCC 700408 and ATCC 14028), in addition to two animal models: Mus musculus (mice) for assessing DMG efficacy and safety in systemic infection, and Galleria mellonella (wax moth larvae) for testing virulence attenuation in an invertebrate model.
What were the most important findings?
This study provides compelling evidence that dimethylglyoxime (DMG), a nickel-specific chelator, exerts a potent bacteriostatic effect against multidrug-resistant Salmonella Typhimurium and Klebsiella pneumoniae by inhibiting key Ni-dependent enzymes—hydrogenase and urease, respectively. At concentrations between 1 and 5 mM, DMG impaired enzyme activity without exhibiting toxicity in murine or invertebrate models. In vivo, DMG administration resulted in 50% survival among infected mice, compared to complete lethality in untreated controls, and led to a 10-fold reduction in bacterial colonization of the liver and spleen. In Galleria mellonella, pre-injection with DMG improved survival by 40–60% after challenge with lethal doses of MDR pathogens. NMR analysis confirmed DMG’s systemic absorption by detecting it in liver tissue. The absence of adverse effects in either model underscores the compound’s therapeutic safety. The targeted suppression of nickel-requiring pathogens supports the utility of metallome-directed interventions in combating MDR infections, particularly for pathogens that rely on nickel-dependent enzymes for virulence.
| Finding | Details |
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| Bacteriostatic Activity | DMG showed concentration-dependent inhibition (1–5 mM) of MDR S. Typhimurium and K. pneumoniae. |
| Target Enzymes | Inhibited hydrogenase activity in Salmonella and urease activity in Klebsiella, both Ni-dependent enzymes. |
| Animal Survival | 50% survival in DMG-treated mice vs. 0% in untreated controls. |
| Organ Burden Reduction | 10-fold reduction in bacterial colonization in livers and spleens of treated mice. |
| Larvae Protection | 40–60% survival in DMG-treated G. mellonella larvae following lethal bacterial challenge. |
| Systemic Bioavailability | NMR confirmed presence of DMG in liver tissue post-oral administration. |
| Safety Profile | No observed toxicity in mice or larvae at therapeutic doses. |
| Mechanistic Relevance | Aligns with a metallomic intervention strategy by targeting Ni-dependent MMAs (Salmonella, Klebsiella). |
What are the greatest implications of this study?
This study underscores the translational potential of metallome-targeted interventions, specifically through nickel chelation, as a viable therapeutic approach against MDR pathogens. By inhibiting bacterial nickel-dependent enzymatic machinery critical for virulence and survival, such as hydrogenases and ureases, DMG offers a mechanism-based strategy that bypasses conventional antibiotic resistance pathways. The fact that many high-priority MDR pathogens identified by the WHO possess Ni-dependent enzymes positions nickel chelation as a broadly applicable antimicrobial modality. Moreover, the non-toxic profile of DMG in two distinct animal models supports its development for clinical use, particularly as an adjunct or alternative to antibiotics in cases of resistant infections.