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Similarly, a recent study identified the nickel requirement for Cryptococcus neoformans’s urease as the fungus’s “Achilles’ heel” 9. For instance, targeting nickel trafficking pathways to inactivate both the H 2-uptake hydrogenase and the urease in the gastric pathogen Helicobacter pylori has been proposed 7, 8. The nickel requirement for enzymes associated only with bacterial (and not host) enzymes has already led several groups of researchers to suggest nickel sequestration as a possible therapeutic target to combat several pathogens 6. Indeed, nickel is required as a cofactor for several bacterial enzymes, including acireductone dioxygenase, -hydrogenase, glyoxalase I, superoxide dismutase and urease 4, 5. Therefore, new avenues to disable these and related pathogens need to be explored: metal chelation, more specifically nickel (Ni) chelation, could be one of them. Resistance to drugs can emerge rapidly, and responses to these emerging public threats are slow or even non existent for instance, there are no treatment guidelines established for patients carrying quinolone-resistant Salmonella Typhi strains 3. A recent study conducted over 3 years in a French hospital found that bloodstream infections with MDR Enterobacteriaceae accounted for more than 70% of all bloodstream infections with MDR bacterial strains 2. In its most recent list of pathogens that require new antibiotics, the World Health Organization (WHO) lists carbapenem-resistant Enterobacteriaceae (CRE) in its highest (critical) priority group 1. Among Enterobacteriaceae, multi-drug resistant (MDR) species pose one of the biggest public health challenges of our time. For instance, in 2013, the annual cost associated with non-typhoidal Salmonella infections alone was estimated at 3.67 billion dollars in the United States (United States Department of Agriculture). Our results suggest that DMG-mediated Ni-chelation could provide a novel approach to combat enteric pathogens, including recalcitrant multi-drug resistant strains.Įvery year, Enterobacteriaceae illnesses, including those by Escherichia, Klebsiella, Salmonella, Shigella and Yersinia species, cost billions of dollars in diarrheal illness treatment and lead to millions of human deaths. Typhimurium led to 40% and 60% survival, respectively, compared to 100% mortality of larvae infected with either pathogen, but without prior DMG administration.
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Inoculation of Galleria mellonella (wax moth) larvae with DMG prior to injection of either MDR K. Using Nuclear Magnetic Resonance, we were able to detect DMG in the livers of DMG-(orally) treated mice. Pathogen colonization numbers from livers and spleens of mice were 10- fold reduced by DMG treatment of the Salmonella-infected mice. Typhimurium led to a 50% survival rate, while 100% of infected mice in the no-DMG control group succumbed to salmonellosis. Oral delivery of nontoxic levels of DMG to mice previously inoculated with S. DMG inhibited activity of two Ni-containing enzymes, Salmonella hydrogenase and Klebsiella urease. 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. With a goal of seeking the balance of research transparency, institutional collaboration and the elimination of duplication, the DIPG / DMG Collaborative funds both clinical and translational research worldwide.The nickel (Ni)-specific chelator dimethylglyoxime (DMG) has been used for many years to detect, quantitate or decrease Ni levels in various environments. The DIPG / DMG Symposium, which occurs every two years, is the culmination of not only the DIPG / DMG Collaborative’s funding cycle, but also features unique perspectives on research from experts around the globe. Originally an organic development of the DIPG / DMG Symposium held in Cincinnati, Ohio, USA in 2011, today the DIPG / DMG Collaborative is made up of more than 20 foundations cooperatively funding between $1,000,000 to $2,000,000 in DIPG/DMG research every two years. The DIPG / DMG Collaborative is a collection of foundations with the common interest of inspiring research into the cure of Diffuse Intrinsic Pontine Glioma (DIPG) and Diffuse Midline Glioma (DMG) with the belief that through a cure for DIPG/DMG, significant advances in other cancer research will be made.