Overcoming antimicrobial resistance – exploiting zinc intoxication to restore antibiotic efficacy — ASN Events

Overcoming antimicrobial resistance – exploiting zinc intoxication to restore antibiotic efficacy (#34)

Erin B. Brazel 1 , Stephanie L. Begg 1 , Bart A. Eijkelkamp 1 , Ibrahim M. El-Deeb 2 , Trent Conroy 2 , James C. Paton 1 , Alastair G. McEwan 3 , Jason W. Rosch 4 , Mark von Itzstein 2 , Mark J. Walker 3 , Christopher A. McDevitt 1
  1. Research Centre for Infectious Diseases, University of Adelaide, Adelaide, SA, Australia
  2. Institute for Glycomics, Griffith University, Southport, QLD, Australia
  3. School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, St Lucia, QLD, Australia
  4. Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, United States

The prevalence of antibiotic resistant pathogens continues to rise and threatens to disrupt healthcare on a global scale. To combat antibiotic resistance, novel strategies for treating bacterial infections are urgently required. The metal ion zinc has a critical role in innate immune defence and its deficiency is associated with a marked increase in susceptibility to bacterial infections. Although the molecular basis for the antimicrobial activity of zinc remains to be elucidated, recent studies have shown that phagocytic cells exploit zinc intoxication as a component of their bacterial clearance mechanisms. Streptococcus pneumoniae (the pneumococcus) is a major cause of local and invasive diseases and is associated with significant human mortality. Despite the importance of zinc at the host-pathogen interface, the impact of zinc stress on S. pneumoniae remains poorly understood. Here, we investigated how zinc stress affected the virulent S. pneumoniae D39 strain using a combination of phenotypic growth, cellular metal accumulation and macrophage survival analyses. These studies revealed that S. pneumoniae encoded a cation diffusion facilitator family transporter (CzcD) that was capable of zinc efflux and contributed to pneumococcal survival within phagocytic cells. We further examined the impact of zinc stress by abolishing czcD functionality. This revealed that zinc intoxication rendered S. pneumoniae more sensitive to specific classes of antibiotics. Building on these findings, we examined synergism between zinc and antibiotics using ionophores to increase the potency of zinc stress. Ionophore-mediated zinc treatment restored antibiotic susceptibility to the multidrug resistant S. pneumoniae 23F strain. Collectively, this study provides detailed insight into zinc resistance in S. pneumoniae and highlights the therapeutic potential of zinc and ionophores as adjuvants to antibiotics as a novel treatment strategy.

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