Abstract
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.
Highlights
Metal ion homeostasis is essential for all forms of life
This effect has previously been ascribed to Cd2+-induced perturbation of cellular accumulation of manganese (Mn2+) and zinc (Zn2+) ions[18], but the extent of the cellular impact of Cd2+ was not fully defined
We propose that the resultant depletion of cellular Zn2+ can be attributed to Cd2+-bound AdcR mimicking the Zn2+-bound state leading to repression of the adc regulon consistent with the downregulation of the Zn2+-recruiting genes adcAII, phtB, phtD, and phtE, (Supplementary Table 3)
Summary
Metal ion homeostasis is essential for all forms of life. the breadth of intracellular impacts that arise upon dysregulation of metal ion homeostasis remain to be elucidated. This study provides new insights into the molecular basis of Cd2+ toxicity, the breadth of impacts that arise from disruption of cellular metal ion homeostasis, and reveals the mitigation strategies that bacteria, such as S. pneumoniae, can employ to survive these chemical stress insults.
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