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However, the staphylococcal adaptations that provide defense against nutritional immunity and the role of metal-responsive regulators are not fully characterized. In this work, we define the transcriptional response of\n                      <jats:italic>S. aureus<\/jats:italic>\n                      and the role of the metal-responsive regulators, Zur, Fur, and MntR, in response to metal limitation by calprotectin exposure. Additionally, we identified genes affecting the fitness of\n                      <jats:italic>S. aureus<\/jats:italic>\n                      during metal limitation through a Transposon sequencing (Tn-seq) approach. Loss of function mutations in\n                      <jats:italic>clpP<\/jats:italic>\n                      , which encodes a proteolytic subunit of the ATP-dependent Clp protease, demonstrate reduced fitness of\n                      <jats:italic>S. aureus<\/jats:italic>\n                      to the presence of calprotectin. ClpP contributes to pathogenesis\n                      <jats:italic>in vivo<\/jats:italic>\n                      in a calprotectin-dependent manner. These studies establish a critical role for ClpP to combat metal limitation by calprotectin and reveal the genes required for\n                      <jats:italic>S. aureus<\/jats:italic>\n                      to outcompete the host for metals.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Staphylococcus aureus<\/jats:italic>\n                      is a leading cause of skin and soft tissue infections, bloodstream infections, and endocarditis. Antibiotic treatment failures during\n                      <jats:italic>S. aureus<\/jats:italic>\n                      infections are increasingly prevalent, highlighting the need for novel antimicrobial agents. Metal chelator-based therapeutics have tremendous potential as antimicrobials due to the strict requirement for nutrient metals exhibited by bacterial pathogens. The high-affinity transition metal-binding properties of calprotectin represents a potential therapeutic strategy that functions through metal chelation. Our studies provide a foundation to define mechanisms by which\n                      <jats:italic>S. aureus<\/jats:italic>\n                      combats nutritional immunity and may be useful for the development of novel therapeutics to counter the ability of\n                      <jats:italic>S. aureus<\/jats:italic>\n                      to survive in a metal-limited environment.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.01389-24","type":"journal-article","created":{"date-parts":[[2024,6,26]],"date-time":"2024-06-26T09:02:48Z","timestamp":1719392568000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":22,"title":["Coordinated adaptation of\n                    <i>Staphylococcus aureus<\/i>\n                    to calprotectin-dependent metal sequestration"],"prefix":"10.1128","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4824-9898","authenticated-orcid":false,"given":"Valeria M.","family":"Reyes Ruiz","sequence":"first","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"name":"Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey A.","family":"Freiberg","sequence":"additional","affiliation":[{"name":"Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"name":"Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andy","family":"Weiss","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"name":"Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin R.","family":"Green","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"name":"Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary-Elizabeth","family":"Jobson","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Felton","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0629-8990","authenticated-orcid":true,"given":"Lindsey N.","family":"Shaw","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter J.","family":"Chazin","sequence":"additional","affiliation":[{"name":"Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"name":"Department of Biochemistry, Vanderbilt University, Nashville, 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