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The PerR-Regulated P1B-4-Type ATPase (PmtA) Acts as a Ferrous Iron Efflux Pump in Streptococcus pyogenes
Andrew G Turner1, Cheryl-Lynn Y Ong1, Karrera Y Djoko1
1School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia.
Abstract:
Streptococcus pyogenes (group A Streptococcus [GAS]) is an obligate human pathogen responsible for a broad spectrum of human disease. GAS has a requirement for metal homeostasis within the human host and, as such, tightly modulates metal uptake and efflux during infection. Metal acquisition systems are required to combat metal sequestration by the host, while metal efflux systems are essential to protect against metal overload poisoning. Here, we investigated the function of PmtA (PerR-regulated metal transporter A), a P1B-4-type ATPase efflux pump, in invasive GAS M1T1 strain 5448. We reveal that PmtA functions as a ferrous iron [Fe(II)] efflux system. In the presence of high Fe(II) concentrations, the 5448ΔpmtA deletion mutant exhibited diminished growth and accumulated 5-fold-higher levels of intracellular Fe(II) than did the wild type and the complemented mutant. The 5448ΔpmtA deletion mutant also showed enhanced susceptibility to killing by the Fe-dependent antibiotic streptonigrin as well as increased sensitivity to hydrogen peroxide and superoxide. We suggest that the PerR-mediated control of Fe(II) efflux by PmtA is important for bacterial defense against oxidative stress. PmtA represents an exemplar for an Fe(II) efflux system in a host-adapted Gram-positive bacterial pathogen.
Insights
Streptococcus pyogenes uses PmtA to export ferrous iron (Fe(II)), preventing toxic overload and protecting against oxidative stress. This metal transporter is crucial for pathogen survival during infection.
Area of Science:
- Microbiology
- Molecular Biology
- Pathogen-Host Interactions
Background:
- Streptococcus pyogenes (GAS) requires metal homeostasis for survival within the human host.
- GAS utilizes metal uptake and efflux systems to manage intracellular metal concentrations during infection.
- Metal efflux systems are critical for protecting bacteria against metal toxicity.
Purpose of the Study:
- To investigate the function of PmtA (PerR-regulated metal transporter A), a P1B-4-type ATPase efflux pump, in the invasive GAS M1T1 strain 5448.
- To determine the role of PmtA in ferrous iron (Fe(II)) homeostasis and oxidative stress response in GAS.
Main Methods:
- Construction and analysis of a PmtA deletion mutant (5448ΔpmtA) in GAS M1T1 strain 5448.
- Measurement of intracellular Fe(II) levels under high Fe(II) conditions.
- Assessment of bacterial growth, susceptibility to Fe-dependent antibiotics (streptonigrin), and sensitivity to oxidative stress (hydrogen peroxide, superoxide).
Main Results:
- PmtA functions as a ferrous iron [Fe(II)] efflux system.
- The 5448ΔpmtA mutant showed diminished growth and accumulated 5-fold higher intracellular Fe(II) compared to wild-type.
- The mutant exhibited increased susceptibility to streptonigrin, hydrogen peroxide, and superoxide.
Conclusions:
- PerR-mediated control of Fe(II) efflux by PmtA is vital for GAS defense against oxidative stress.
- PmtA is an important Fe(II) efflux system in the host-adapted pathogen Streptococcus pyogenes.
- Understanding PmtA function provides insights into metal homeostasis mechanisms in bacterial pathogens.