Inhibiting hydrogen-dependent pathogen growth via nickel chelation

总结 沙门氏菌和其他病原体利用宿主微生物群产生的分子氢（H2）， 在宿主体内生长;它们通过保守的含镍氢化酶这样做。一 提出了一种新的探索性方法来评估天然组氨酸的能力， 含半胱氨酸的金属结合肽来对抗沙门氏菌病。理由是基于 镍螯合化学品对沙门氏菌氢化酶的有效性 表达，甚至在小鼠中的沙门氏菌病。然而，已知的螯合剂对人是有毒的。 动物相反，具有固有的高镍结合能力的小肽将被 首先评估它们在实验室中抑制病原体的H2依赖性生长的能力， 然后在动物体内。镍对H2依赖性生长的抑制程度 剥夺将分配给个别氢利用氢化酶通过研究 突变株螯合剂的分子性质，包括Ni结合结构域的使用 融合，以及纳米粒子主机交付制度将进行研究，以充分评估 沙门氏菌抑制作用。测试由已识别的 镍螯合域预计将提高螯合剂（镍结合）的有效性， mg的肽，同时将它们包封在可生物降解的聚合物胶束中， 促进它们的胃存活，因此它们在体内的有效性可以在 探索之路对于体内测试，在小肠中进行基于肽的螯合， 沙门氏菌生长迅速，并依赖于H2通过一个确定的镍氢化酶， 需要的话这项工作预计将适用于生长衰减镍需要肠 致病菌包括沙门氏菌、志贺氏菌、肠杆菌E.大肠杆菌和弯曲杆菌， 新的金属螯合剂的开发可应用于医学的许多领域。

Summary Salmonella and other pathogens use host microbiota-produced molecular hydrogen (H2) to grow within the host; they do so via conserved nickel-containing hydrogenase enzymes. A new exploratory approach is proposed to assess the ability of natural histidine- and cysteine-containing metal-binding peptides to combat salmonellosis. The rationale is based on the effectiveness of nickel chelating chemicals to attenuate Salmonella hydrogenase expression and even salmonellosis in mice. However, the known chelators are toxic to the animal. Instead, small peptides that have inherently high capacity for nickel binding will be assessed first for their ability to inhibit H2 dependent growth of the pathogen in the lab and then within the animal. The degree of inhibition of H2-dependent growth by nickel deprivation will be assigned to individual hydrogen-utilizing hydrogenases by studying mutant strains. The molecular nature of the chelator, including use of Ni-binding domain fusions, as well as the nanoparticle host delivery regimes will be studied to fully assess the salmonella-inhibitory affects. Testing of truncated and fused versions composed of identified Ni-sequestering domains is expected to improve chelator (nickel-binding) effectiveness per mg of peptide, while encapsulating them in biodegradable polymeric micelles is expected to promote their gastric survival so their effectiveness in vivo can be assessed in an exploratory way. For in vivo testing, peptide-based chelation in the small intestine where Salmonella growth is rapid and dependent on H2 via an identified Ni-hydrogenase is desired. The work is expected to apply to growth attenuation of nickel-requiring enteric pathogens, including Salmonella, Shigella, enterotoxigenic E. coli, and Campylobacter, but the new metal chelator development may apply to many areas of medicine.