Host subversion of bacterial metallophore usage drives copper intoxication

Author:

Hossain Saika1,Morey Jacqueline R.1,Neville Stephanie L.2,Ganio Katherine2,Radin Jana N.1,Norambuena Javiera3,Boyd Jeff M.3,McDevitt Christopher A.2,Kehl-Fie Thomas E.14ORCID

Affiliation:

1. Department of Microbiology, University of Illinois at Urbana-Champaign , Urbana, Illinois, USA

2. Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne , Melbourne, Victoria, Australia

3. Department of Biochemistry and Microbiology, Rutgers University , New Brunswick, New Jersey, USA

4. Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign , Urbana, Illinois, USA

Abstract

ABSTRACT Microorganisms can acquire metal ions in metal-limited environments using small molecules called metallophores. While metals and their importers are essential, metals can also be toxic, and metallophores have limited ability to discriminate between metals. The impact of metallophore-mediated non-cognate metal uptake on bacterial metal homeostasis and pathogenesis remains to be defined. The globally significant pathogen Staphylococcus aureus uses the Cnt system to secrete the metallophore staphylopine in zinc-limited host niches. Here, we show that staphylopine and the Cnt system facilitate bacterial copper uptake, potentiating the need for copper detoxification. During in vivo infection, staphylopine usage increased S. aureus susceptibility to host-mediated copper stress, indicating that the innate immune response can harness the antimicrobial potential of altered elemental abundances in host niches. Collectively, these observations show that while the broad-spectrum metal-chelating properties of metallophores can be advantageous, the host can exploit these properties to drive metal intoxication and mediate antibacterial control. IMPORTANCE During infection, bacteria must overcome the dual threats of metal starvation and intoxication. This work reveals that the zinc-withholding response of the host sensitizes S. aureus to copper intoxication. In response to zinc starvation, S. aureus utilizes the metallophore staphylopine. The current work revealed that the host can leverage the promiscuity of staphylopine to intoxicate S. aureus during infection. Significantly, staphylopine-like metallophores are produced by a wide range of pathogens, suggesting that this is a conserved weakness that the host can leverage to toxify invaders with copper. Moreover, it challenges the assumption that the broad-spectrum metal binding of metallophores is inherently beneficial to bacteria.

Funder

HHS | National Institutes of Health

Department of Education and Training | Australian Research Council

DHAC | National Health and Medical Research Council

U.S. Department of Agriculture

Passe and Willams Fellowship

Chester W. and Nadine C. Houston Endowment Fellowship

The Vallee Foundation

Publisher

American Society for Microbiology

Subject

Virology,Microbiology

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