Nickel

Overview

Nickel (Ni) is a ubiquitous trace metal present in soil, water, foods, and many consumer products.^[1] In humans, nickel has been commonly associated with hypersensitivity reactions, particularly nickel-induced contact dermatitis. Recent studies have suggested that nickel hypersensitivity might be linked to conditions such as endometriosis and irritable bowel syndrome (IBS). While it has no known essential biochemical role in humans, it is required by numerous microorganisms for key enzymes that influence metabolism and virulence.^[2] Understanding these mechanisms opens pathways for potential therapeutic interventions, such as targeting nickel acquisition or the activity of these enzymes to limit pathogen survival and virulence, and improve host health.

Nickel in Microbial Metabolism and Virulence

Many pathogenic microbes rely on Ni as a cofactor for enzymes that enhance their survival and virulence. In fact, at least 39 major bacterial and 9 eukaryotic pathogens are known to require Ni for various enzymes – including urease, [NiFe] hydrogenase, Ni-dependent glyoxalase I (Ni-GloI), acireductone dioxygenase (Ni-ARD), and Ni-superoxide dismutase (Ni-SOD) – whereas human hosts do not require Ni for any enzyme.^[4] This host-pathogen disparity presents a therapeutic opportunity: selective nickel sequestration—by targeting the pathogen’s unique reliance on Ni-dependent enzymes—disrupts microbial virulence while sparing host physiology, exemplifying a precise and effective form of metallomic targeting.^[5] Key Ni-dependent microbial pathways include:

Ni-dependent microbial pathways	Function
Urease	Urease is a Ni-dependent enzyme essential for acid neutralization in H. pylori, Proteus, and Klebsiella, enabling colonization of the stomach or urinary tract. In H. pylori, urease (and Ni–Fe hydrogenase) is so critical that standard therapy may fail if nickel is abundant. A pilot trial found that adding a Ni-free diet to triple therapy increased eradication rates from 46% to 85% (22/26 vs. 12/26, p<0.01). The mechanism is Ni restriction suppressing urease, lowering pH resistance and boosting antibiotic efficacy.^[6]
[NiFe] Hydrogenase	[NiFe] hydrogenase is a Ni-dependent enzyme that enables H. pylori and Salmonella to use H₂ as an energy source and is a documented virulence factor.^[7] In H. pylori, this enzyme promotes gastric colonization and growth, while ∆hyd mutants show reduced colonization (24% vs. 100%) and fail to translocate the CagA oncoprotein or induce cancer in models.^[8] A low-nickel diet suppresses this pathway by depriving hydrogenase of Ni, forcing H. pylori to triage Ni between hydrogenase and urease, potentially attenuating H. pylori’s acid resistance and virulence, simultaneously.^[9]
Acireductone Dioxygenase (ARD)	Acireductone dioxygenase (ARD) is a methionine salvage enzyme that uses either Fe²⁺ or Ni²⁺, generating different products: Ni-ARD produces toxic CO and methylthiopropionate, while Fe-ARD yields formate and a methionine precursor. Pathogenic Enterobacteriaceae and other γ-proteobacteria, including Klebsiella, Pseudomonas, and Acinetobacter, predominantly encode Ni-ARD, which is absent in eukaryotes. LNiD may shift ARD activity toward the less virulent Fe-bound form or impair ARD entirely, disrupting methionine salvage and bacterial signaling.^[10]
Ni-Glyoxalase I (Ni-GloI)	Ni-Glyoxalase I (Ni-GloI) detoxifies methylglyoxal, a toxic byproduct, and is used by many pathogens including E. coli, Pseudomonas, Neisseria, Yersinia, and Clostridium. Unlike the Zn²⁺-dependent form found in humans, these microbes rely on Ni-GloI for survival under stress. Disrupting Ni-GloI impairs detoxification and viability, as shown in Leishmania. LNiD may reduce microbial stress tolerance by limiting Ni and re-sensitizing pathogens to their own metabolic toxins.^[11]
Ni-Superoxide Dismutase (Ni-SOD)	Ni-Superoxide Dismutase (Ni-SOD) is a rare SOD variant found in some bacteria, such as Streptomyces spp., but not in mammals. It enables pathogens to resist oxidative bursts from immune cells. While most pathogens use Mn- or Fe-SOD, some, like Streptomyces scabies, rely specifically on Ni-SOD . LNiD may impair these pathogens’ antioxidant defenses by limiting Ni availability, reducing their resistance to host immunity. ^[12]
Biofilm Formation and Antimicrobial Resistance	Chronic nickel exposure promotes bacterial adaptation via increased adhesion, biofilm formation, and antibiotic resistance, as shown in E. coli and others. Nickel acts as a stress signal that upregulates biofilm-related genes, enhancing microbial protection. Conversely, a low-nickel diet may reduce biofilm formation by lowering Ni availability, shifting the gut microbiota away from Ni-tolerant, drug-resistant opportunists and favoring benign commensals. ^[13]
Methanogenic Archaea	Methanogenic archaea such as Methanobrevibacter smithii, linked to constipation-predominant irritable bowel syndrome IBS, require Ni-containing enzymes like methyl-coenzyme M reductase with the F430 cofactor for methanogenesis. Ni is essential for their growth, and excess Ni may drive methane production, slowing gut transit and causing bloating. A low-nickel diet suppresses these archaea and reduce methane-associated GI symptoms, though clinical evidence is still emerging. ^[14]

Host Strategies to Limit Nickel Availability

Nickel plays a crucial role in the virulence of certain pathogens due to its necessity for enzymes like ureases and hydrogenases, yet its scarcity in the host environment poses a challenge for microbial acquisition. This scarcity is a function of nutritional immunity, where the host limits access to metals such as iron, zinc, and, nickel to suppress pathogen growth. Host defense proteins like calprotectin, lactoferrin, and hepcidin contribute to this metal sequestration, particularly at sites of inflammation where neutrophils release these proteins. Notably, calprotectin, traditionally known for zinc binding, has been shown to preferentially bind nickel at its hexahistidine site, effectively inhibiting nickel-dependent enzymatic activity in pathogens like Staphylococcus aureus and Klebsiella pneumonia. ^[15] This interaction highlights a critical mechanism by which host defenses limit microbial virulence and presents a promising target for novel antimicrobial strategies.

Nickel Chelation Strategies

Agent	Findings and Implications
Lactoferrin	Lactoferrin, a multifunctional globular protein, exhibits antimicrobial activity partly through iron chelation. Notably, its histidine and tyrosine residues also enable it to bind other metals, including nickel. ^[16] This suggests lactoferrin may impair nickel-dependent pathogens by sequestering nickel, extending its utility beyond iron-targeted antimicrobial effects. Its therapeutic potential may include treatment of infections involving nickel-reliant enzymes (e.g., ureases, hydrogenases), positioning it as a dual-action antimicrobial agent.
Dimethylglyoxime (DMG)	Dimethylglyoxime (DMG) is a high-affinity nickel chelator that has demonstrated effectiveness in inhibiting nickel-dependent enzymes such as hydrogenases and ureases. In preclinical models, it significantly reduced virulence and colonization of multidrug-resistant pathogens like Salmonella Typhimurium and Klebsiella pneumonia. These findings support DMG’s potential as a novel antimicrobial agent targeting metal-dependent virulence pathways. Ni-chelation therapies such as DMG could represent a new class of antimicrobials— better described as bacteriostatics—with efficacy against resistant enteric pathogens. ^[17]

Agent

Findings and Implications

Lactoferrin

Lactoferrin, a multifunctional globular protein, exhibits antimicrobial activity partly through iron chelation. Notably, its histidine and tyrosine residues also enable it to bind other metals, including nickel. ^[16] This suggests lactoferrin may impair nickel-dependent pathogens by sequestering nickel, extending its utility beyond iron-targeted antimicrobial effects. Its therapeutic potential may include treatment of infections involving nickel-reliant enzymes (e.g., ureases, hydrogenases), positioning it as a dual-action antimicrobial agent.

Dimethylglyoxime (DMG)

Dimethylglyoxime (DMG) is a high-affinity nickel chelator that has demonstrated effectiveness in inhibiting nickel-dependent enzymes such as hydrogenases and ureases. In preclinical models, it significantly reduced virulence and colonization of multidrug-resistant pathogens like Salmonella Typhimurium and Klebsiella pneumonia. These findings support DMG’s potential as a novel antimicrobial agent targeting metal-dependent virulence pathways. Ni-chelation therapies such as DMG could represent a new class of antimicrobials— better described as bacteriostatics—with efficacy against resistant enteric pathogens. ^[17]

Implications for Research and Therapeutics

Understanding the mechanisms of nickel acquisition, transport, and regulation in pathogens, alongside the characterization of Ni-dependent enzymes, offers potential avenues for developing new therapeutic strategies. Targeting nickel transport systems or the maturation and activity of Ni-dependent virulence factors could provide a novel means of combating infections, particularly for pathogens where the metal plays a crucial role in survival and pathogenicity. The recognition that Ni-requiring enzymes are important for the virulence of a diverse array of both prokaryotic and eukaryotic pathogens emphasizes the need for further research into microbial metallomics in microbial pathogenesis. Investigating the potential pathogenic roles of newly identified Ni-binding components, informed by recent experimental data, can expand our understanding of microbial virulence mechanisms and reveal new targets for intervention. The dependency of certain pathogens on nickel ions for vital enzymatic processes directly linked to virulence factors highlights the complex interplay between microbial metabolism and pathogenicity. The study of nickel in microbial pathogenesis not only offers insights into the basic biology of pathogens but also opens up potential therapeutic avenues aimed at disrupting metal homeostasis to combat infections.

MBTIs

Various strategies for nickel chelation may offer promise as a treatment for the aforementioned eukaryotic and prokaryotic microorganisms featuring nickel-dependent enzymes. Dimethylglyoxime (DMG) has already been investigated as a potent nickel chelation therapy to combat multi-drug resistant enteric pathogens, including multi-drug resistant strains of Salmonella Typhimurium and Klebsiella pneumonia.^[18]

Theoretical Foundation

As an essential cofactor for critical enzymes such as hydrogenase and urease, Ni has established roles in microbial pathogenic processes. However, the scope of nickel’s involvement in pathogens with other nickel-requiring enzymes warrants further exploration. Additional nickel-utilizing proteins, or those responding to nickel concentration changes, are anticipated to be identified. It is vital to address the gaps in our understanding of nickel dynamics and its regulation within pathogens that require this metal. This includes delineating the origins of dietary nickel, how host metabolism influences its availability to pathogens and the effect of host gut microbiota composition on nickel presence. Investigating these areas is crucial for advancing our knowledge. The variability of nickel’s accessibility in the host is notable, necessitating a deeper understanding of its general availability across various organs, tissues, and cell types, such as epithelial, immune, and blood cells. One promising research direction is the unique requirement of nickel by numerous pathogens—at leat 39 prokaryotic and nine eukaryotic—unlike their mammalian hosts.^[19] This discrepancy presents the possibility of specifically targeting these pathogens through nickel sequestration strategies.

Research Feed

September 25, 2019

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