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

EB Brazel; A Tan; SL Neville; AR Iverson; SR Udagedara; BA Cunningham; M Sikanyika; DMP De Oliveira; B Keller; L Bohlmann; IM El-Deeb; K Ganio; BA Eijkelkamp; AG McEwan; M von Itzstein; MJ Maher; MJ Walker; JW Rosch; CA McDevitt

Journal article

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

EB Brazel, A Tan, SL Neville, AR Iverson, SR Udagedara, BA Cunningham, M Sikanyika, DMP De Oliveira, B Keller, L Bohlmann, IM El-Deeb, K Ganio, BA Eijkelkamp, AG McEwan, M von Itzstein, MJ Maher, MJ Walker, JW Rosch, CA McDevitt

Cell Reports | Published : 2022

DOI: 10.1016/j.celrep.2021.110202

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Abstract

Streptococcus pneumoniae is the primary cause of community-acquired bacterial pneumonia with rates of penicillin and multidrug-resistance exceeding 80% and 40%, respectively. The innate immune response generates a variety of antimicrobial agents to control infection, including zinc stress. Here, we characterize the impact of zinc intoxication on S. pneumoniae, observing disruptions in central carbon metabolism, lipid biogenesis, and peptidoglycan biosynthesis. Characterization of the pivotal peptidoglycan biosynthetic enzyme GlmU indicates a sensitivity to zinc inhibition. Disruption of the sole zinc efflux pathway, czcD, renders S. pneumoniae highly susceptible to β-lactam antibiotics. To d..

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University of Melbourne Researchers

Aimee Tan Author

Stephanie Neville Author

Saumya Udagedara Author

Bliss Cunningham Author

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Grants

Awarded by Australian Cancer Research Foundation

Funding Acknowledgements

This work was supported by the National Health and Medical Research Council (NHMRC) Project Grants 1080784 and 1140554 to C.A.M. and M.J.M., 1176180 and 1194130 to M.J.W., 1071659 to M.J.W. and M.V.I., and 1122582 to C.A.M. and the Australian Research Council (ARC) Discovery Project Grant DP170102102 to C.A.M. Thisworkwas also supported by the National Institutes of Health grants (1U01AI124302 and 1RO1AI110618) to J.W.R. S.L.N. is an NHMRC Early Career Research Fellow (1142695) and C.A.M. and M.J.M. are ARC Future Fellows (FT170100006 and FT180100397, respectively). Part of this studywas carried out using the MX2 beamline at the Australian Synchrotron, which is part of Australian Nuclear Science and Technology Organization (ANSTO) and made use of the Australian Cancer Research Foundation (ACRF) Detector. We thank the beamline staff for their enthusiastic and professional support, Prof. Jan-Willem Veening (University of Lausanne) for provision of the hlpA fluorescent construct and Prof. Michael Caparon (Washington University) for the pABG5-3 mini plasmid.