Inhibiting hydrogen-dependent pathogen growth via nickel chelation

摘要 沙门氏菌和其他病原体使用宿主微生物群产生的分子氢(H2)来 在宿主内生长；它们通过保守的含镍氢酶做到这一点。一个 提出了一种新的探索性方法来评估天然组氨酸-和 含有半胱氨酸的金属结合肽，用于抗击沙门氏菌病。其基本原理是 镍络合剂对沙门氏菌氢酶抑制作用的研究 在小鼠体内的表达，甚至沙门氏菌病。然而，已知的螯合剂对 动物。取而代之的是，具有高镍结合能力的小肽 首先在实验室评估它们抑制依赖氢的病原体生长的能力，并 然后在动物体内。镍对氢依赖生长的抑制程度 通过研究，将剥夺分配给单个利用氢气的氢酶 突变菌株。螯合剂的分子性质，包括镍结合结构域的使用 将研究融合以及纳米颗粒宿主递送制度，以充分评估 沙门氏菌抑制作用。由标识组成的截断和融合版本的测试 镍隔离结构域有望提高螯合剂(镍结合)的有效性 Mg的多肽，同时将它们包裹在可生物降解的聚合物胶束中，有望 促进他们的胃存活，这样他们在体内的有效性可以被评估 探索性方式。对于体内测试，基于多肽的螯合作用在小肠中 沙门氏菌生长迅速，并依赖于氢通过一种已确定的镍氢酶IS 想要。这项工作有望应用于需要镍的肠道细菌的生长衰减 病原体，包括沙门氏菌、志贺氏菌、产肠毒素大肠杆菌和弯曲杆菌，但 新的金属络合剂的开发可能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.