Colloidal bismuth subcitrate impedes proton entry into Helicobacter pylori and increases the efficacy of growth-dependent antibiotics.
Colloidal bismuth subcitrate impedes proton entry into Helicobacter pylori and increases the efficacy of growth-dependent antibiotics.
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DOI：
10.1111/apt.13346
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发表时间：
2015-10
影响因子：
7.6
通讯作者：
Scott DR
中科院分区：
文献类型：
--
作者：
Marcus EA;Sachs G;Scott DR
成功根除幽门螺杆菌正变得越来越困难，主要是因为出现了抗生素耐药性。含铋的治疗方案已经提高了疗效，但其机制尚不清楚。幽门螺杆菌是一种嗜中性细菌，通过酸驯化适应酸性胃环境，但在中性pH下表现出更强劲的生长。许多用于治疗幽门螺杆菌的抗生素依赖于细菌的生长。探讨含铋幽门螺杆菌治疗方案提高疗效的机制。在加入和不加入胶体次柠檬酸铋(CBS)的情况下，分别测定RNAseq和qPCR、通透性细菌和完整细菌中的尿素酶活性、内部pH和膜电位。用CBS和/或氨苄西林评估细菌存活率。与新陈代谢和生长相关的基因在酸性pH条件下被CBS上调。在CBS存在下，在pH为7.4和4.5的条件下，通透性幽门螺杆菌的尿素酶活性降低，而完整的尿素酶活性仅在酸性条件下降低。体外酸化对细胞质pH的影响可被CBS抑制。在酸性介质中加入尿素，膜电位的增加不受CBS的影响。CBS和氨苄西林对幽门螺杆菌存活率的影响比单独使用这两种药物都要大。铋不直接作用于尿素酶或尿素通道。CBS阻止质子进入细菌，导致细胞质pH预期下降。随着细胞质的pH保持在中性细胞代谢活性增加的范围内，依赖生长的抗生素的效力就会增强。
Successful eradication of Helicobacter pylori is becoming more difficult, mainly due to emerging antibiotic resistance. Treatment regimens containing bismuth have increased efficacy, but the mechanism is unknown. H. pylori is a neutralophile adapted to survive the acidic gastric environment via acid acclimation, but demonstrates more robust growth at neutral pH. Many antibiotics used to treat H. pylori rely on bacterial growth. To investigate the mechanism of increased efficacy of bismuth-containing H. pylori treatment regimens. RNAseq and qPCR, urease activity in permeabilized and intact bacteria, internal pH, and membrane potential were measured with and without colloidal bismuth subcitrate (CBS). Bacterial survival was assessed with CBS and/or ampicillin. Genes involved with metabolism and growth were upregulated in the presence of CBS at acidic pH. Urease activity of permeabilized H. pylori at pH 7.4 and 4.5 decreased in the presence of CBS, but intact urease activity only decreased at acidic pH. The fall in cytoplasmic pH with external acidification was diminished by CBS. The increase in membrane potential in response to urea addition at acidic medium pH was unaffected by CBS. The impact of CBS and ampicillin on H. pylori survival was greater than either agent alone. Bismuth is not acting directly on urease or the urea channel. CBS impedes proton entry into the bacteria, leading to a decrease in the expected fall in cytoplasmic pH. With cytoplasmic pH remaining within range for increased metabolic activity of a neutralophile, the efficacy of growth dependent antibiotics is augmented.