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

Erin B. Brazel, Aimee Tan, Stephanie L. Neville, Amy R. Iverson, Saumya R. Udagedara, Bliss A. Cunningham, Mwilye Sikanyika, David M.P. De Oliveira, Bernhard Keller, Lisa Bohlmann, Ibrahim M. El-Deeb, Katherine Ganio, Bart A. Eijkelkamp, Alastair G. McEwan, Mark von Itzstein, Megan J. Maher, Mark J. Walker, Jason W. Rosch, Christopher A. McDevitt

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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 dysregulate zinc homeostasis in the wild-type strain, we investigated the safe-for-human-use ionophore 5,7-dichloro-2-[(dimethylamino)methyl]quinolin-8-ol (PBT2). PBT2 rendered wild-type S. pneumoniae strains sensitive to a range of antibiotics. Using an invasive ampicillin-resistant strain, we demonstrate in a murine pneumonia infection model the efficacy of PBT2 + ampicillin treatment. These findings present a therapeutic modality to break antibiotic resistance in multidrug-resistant S. pneumoniae.

Original languageEnglish
Article number110202
Number of pages18
JournalCell Reports
Volume38
Issue number2
DOIs
Publication statusPublished - 11 Jan 2022

Keywords

  • antibiotics
  • antimicrobial resistance
  • bacterial pathogen
  • ionophore
  • multidrug resistance
  • PBT2
  • Streptococcus pneumoniae
  • zinc
  • zinc intoxication

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