Dysregulation of transition metal ion homeostasis is the molecular basis for cadmium toxicity in Streptococcus pneumoniae.
Cadmium is a transition metal ion that is highly toxic in biological systems. Although relatively rare in the Earth's crust, anthropogenic release of cadmium since industrialization has increased biogeochemical cycling and the abundance of the ion in the biosphere. Despite this, the molecular basis of its toxicity remains unclear. Here we combine metal-accumulation assays, high-resolution structural data and biochemical analyses to show that cadmium toxicity, in Streptococcus pneumoniae, occurs via perturbation of first row transition metal ion homeostasis. We show that cadmium uptake reduces the millimolar cellular accumulation of manganese and zinc, and thereby increases sensitivity to oxidative stress. Despite this, high cellular concentrations of cadmium (~17 mM) are tolerated, with negligible impact on growth or sensitivity to oxidative stress, when manganese and glutathione are abundant. Collectively, this work provides insight into the molecular basis of cadmium toxicity in prokaryotes, and the connection between cadmium accumulation and oxidative stress.
Research Centre for Infectious Diseases, School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 4072, Australia.
Stephanie L
SL
Begg
Research Centre for Infectious Diseases, School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 4072, Australia.
Bart A
BA
Eijkelkamp
1] School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4072, Australia [2] Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Queensland 4072, Australia [3] Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
Zhenyao
Z
Luo
1] School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4072, Australia [2] Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Queensland 4072, Australia [3] Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
Rafael M
RM
Couñago
Research Centre for Infectious Diseases, School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 4072, Australia.
Jacqueline R
JR
Morey
La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia.
Megan J
MJ
Maher
1] School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4072, Australia [2] Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Queensland 4072, Australia.
Cheryl-Lynn Y
CL
Ong
1] School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4072, Australia [2] Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Queensland 4072, Australia.
Alastair G
AG
McEwan
1] School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4072, Australia [2] Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Queensland 4072, Australia [3] Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
Bostjan
0000000194139166
B
Kobe
1] School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4072, Australia [2] School of Mathematics and Physics, University of Queensland, Brisbane, Queensland 4072, Australia.
Megan L
ML
O'Mara
Research Centre for Infectious Diseases, School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 4072, Australia.
James C
JC
Paton
Research Centre for Infectious Diseases, School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 4072, Australia.
Christopher A
CA
McDevitt
D018829:Adhesins, Bacterial / Q000737:chemistry / Q000378:metabolism; D002104:Cadmium / Q000378:metabolism* / Q000633:toxicity*; D003460:Crystallization; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D015151:Immunoblotting; D008074:Lipoproteins / Q000737:chemistry / Q000378:metabolism; D008274:Magnesium / Q000378:metabolism; D008958:Models, Molecular; D018384:Oxidative Stress / Q000187:drug effects*; D011487:Protein Conformation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism
D018829:Adhesins, Bacterial; D008074:Lipoproteins; C085000:PsaA protein, Streptococcus; D002104:Cadmium; D008274:Magnesium; D015032:Zinc