H. pylori utilizes membrane vesicles as a novel tool to extrude bismuth drug

Antibiotic resistance is one of the major threats to human health. Combination of antibiotics with metals is among the proposed alternative treatments. However, so far only one such combination with the metal bismuth successfully used in clinics against Helicobacter pylori. This bacterial pathogen colonizes the human stomach potentially resulting in gastric cancer that causes 800,000 deaths every year. The effect of bismuth on H. pylori is not understood, for sub-lethal doses, such as those present in the plasma of treated patients. We addressed this question and observed that bismuth induces the formation of homogeneous membrane vesicles (MVs) with unique protein cargo content enriched in bismuth-binding proteins. To our surprise, MVs concentrate bismuth, unlike bacterial cells from which they originate. Our results revealed a novel function of MVs in metal detoxification where bismuth is accumulated to discard it from bacteria. Polyphosphate granules (poly-P) formed upon bismuth exposure are associated with changes in nucleoid structure and cell segregation. Thus, even low doses of bismuth induce profound changes in H. pylori physiology and highlight novel defense mechanisms employed by bacteria against bismuth toxicity.

抗生素耐药性是威胁人类健康的主要威胁之一。将抗生素与金属联合使用，是目前被提出的替代治疗方案之一。然而截至目前，仅有铋与抗生素的联合疗法成功应用于临床，用于对抗幽门螺杆菌（Helicobacter pylori，简称H. pylori）。该细菌病原体可定植于人体胃部，有可能引发胃癌，每年造成80万人死亡。目前对于亚致死剂量铋（即接受治疗的患者血浆中存在的铋浓度）作用于H. pylori的机制仍不明晰。本研究针对这一问题展开探索，观察到铋可诱导形成均质膜囊泡（membrane vesicles，简称MVs），其蛋白载荷组成独特，富含铋结合蛋白。令我们意外的是，相较于其来源的细菌细胞，MVs能够富集铋。本研究结果揭示了MVs在金属解毒过程中的全新功能：细菌可通过MVs积累铋并将其排出体外。铋暴露后形成的多磷酸颗粒（polyphosphate granules，简称poly-P）与拟核结构改变及细胞分裂分离异常相关。综上，即使是低剂量的铋也可引发H. pylori生理的深刻变化，凸显了细菌对抗铋毒性的新型防御机制。