Dysregulation of Streptococcus pneumoniae zinc homeostasis breaks ampicillin resistance in a pneumonia infection model

Streptococcus pneumoniae is the primary cause of community-acquired bacterial pneumonia with rates of penicillin and multi-drug resistance exceeding 80% and 40%, respectively. The innate immune response generates a variety of antimicrobial agents to control infection including zinc stress. Here, we characterized the impact of zinc intoxication on S. pneumoniae, revealing disruptions in central carbon metabolism, lipid biogenesis and peptidoglycan biosynthesis. Characterization of the pivotal peptidoglycan biosynthetic enzyme GlmU revealed an exquisite sensitivity to zinc inhibition. Disruption of the sole zinc efflux pathway, czcD, rendered S. pneumoniae highly susceptible to β-lactam antibiotics. To dysregulate zinc homeostasis in the wild-type strain, we investigated the safe-for-human use ionophore PBT2. PBT2 rendered wild-type S. pneumoniae strains sensitive to a range of antibiotics. Using an invasive ampicillin-resistant strain, we demonstrate in a murine pneumonia infection model the efficacy of PBT2+ampicillin treatment. These findings present a therapeutic modality to break resistance of drug-resistant S. pneumoniae.

肺炎链球菌（Streptococcus pneumoniae）是社区获得性细菌性肺炎的主要致病菌，其青霉素耐药率与多重耐药率分别超过80%与40%。固有免疫应答可产生多种抗菌物质以控制感染，其中包括锌胁迫。本研究解析了锌中毒对肺炎链球菌的影响，发现其可干扰中心碳代谢、脂质生物合成与肽聚糖生物合成过程。对关键肽聚糖合成酶GlmU的表征显示，该酶对锌抑制具有极高敏感性。敲除唯一的锌外排通路czcD后，肺炎链球菌对β-内酰胺类抗生素的敏感性显著升高。为扰乱野生型菌株的锌稳态，我们测试了经证实对人体安全的离子载体PBT2：PBT2可使野生型肺炎链球菌对多种抗生素产生敏感性。使用一株侵袭性氨苄西林耐药菌株，我们在小鼠肺炎感染模型中验证了PBT2联合氨苄西林疗法的疗效。本研究成果为破解耐药肺炎链球菌的耐药性提供了一种治疗策略。