Metal ion homeostasis is essential for all forms of life. However, the breadth of intracellular impacts that arise upon dysregulation of metal ion homeostasis remain to be elucidated. Here, we used cadmium, a non-physiological metal ion, to investigate how the bacterial pathogen, Streptococcus pneumoniae, resists metal ion stress and dyshomeostasis. By combining transcriptomics, metabolomics and metalloproteomics, we reveal that cadmium stress dysregulates numerous essential cellular pathways including central carbon metabolism, lipid membrane biogenesis and homeostasis, and capsule production at the transcriptional and/or functional level. Despite the breadth of cellular pathways susceptible to metal intoxication, we show that S. pneumoniae is able to maintain viability by utilizing cellular pathways that are predominately metal-independent, such as the pentose phosphate pathway to maintain energy production. Collectively, this work provides insight into the cellular processes impacted by cadmium and how resistance to metal ion toxicity is achieved in S. pneumoniae.

金属离子稳态对于所有形式的生命都是必不可少的。然而，由金属离子稳态失调引起的细胞内影响的广度仍有待阐明。在这里，我们使用非生理性金属离子镉来研究细菌病原体肺炎链球菌如何抵抗金属离子应力和动态平衡。通过结合转录组学，代谢组学和金属代谢组学，我们揭示了镉胁迫在转录和/或功能水平上失调了许多重要的细胞途径，包括中央碳代谢，脂质膜的生物发生和体内平衡以及胶囊的产生。尽管易受金属中毒影响的细胞途径广泛，但我们显示肺炎链球菌通过利用主要与金属无关的细胞途径（例如磷酸戊糖途径）来维持能量产生，该细胞能够维持活力。总的来说，这项工作提供了对受镉影响的细胞过程的了解，以及如何在肺炎链球菌中获得了对金属离子毒性的抗性。