Journal article
The innate immune protein calprotectin ablates the bactericidal activity of β-lactam antibiotics
Proceedings of the National Academy of Sciences - PNAS, Vol.123(3), e2513462123
01/20/2026
DOI: 10.1073/pnas.2513462123
PMCID: PMC12818397
PMID: 41533443
Abstract
β-lactam antibiotics are among the most widely used treatments for bacterial infections, yet therapeutic failure is common even when no genetic resistance is detected. Understanding how host factors influence antibiotic efficacy is critical for improving outcomes. Here, we identify a host-derived mechanism of antibiotic tolerance mediated by calprotectin (CP), a zinc-binding protein released in large quantities by neutrophils during infection. We show that CP induces tolerance to β-lactam antibiotics in Staphylococcus aureus by chelating zinc and inactivating autolysins, zinc-dependent enzymes required for cell wall degradation and bacterial lysis following β-lactam treatment. This protective effect was specific to β-lactam antibiotics at concentrations of CP showing minimal impact on bacterial growth or metabolic state. Mechanistic studies revealed that CP inhibits the autolytic activity of Atl, the major S. aureus autolysin, by depriving the enzyme of its zinc cofactor. In a murine infection model, the efficacy of oxacillin was significantly enhanced in CP-deficient mice, demonstrating that CP impairs β-lactam activity in vivo. These findings reveal a form of immune-mediated antibiotic tolerance driven by metal sequestration and suggest that zinc availability at infection sites plays a critical role in shaping treatment outcomes.mpairs β-lactam activity in vivo. These findings reveal a form of immune-mediated antibiotic tolerance driven by metal sequestration and suggest that zinc availability at infection sites plays a critical role in shaping treatment outcomes.
Details
- Title: Subtitle
- The innate immune protein calprotectin ablates the bactericidal activity of β-lactam antibiotics
- Creators
- Amanda Z Velez - University of North Carolina at Chapel HillJana N Radin - University of IowaEmily N Kennedy - University of North Carolina at Chapel HillJoshua B Parsons - Duke UniversityHeather M Tong - University of North Carolina at Chapel HillEmma Jung - University of North Carolina at Chapel HillEmily Alam - University of North Carolina at Chapel HillLauren C Radlinski - University of California, DavisNikki J Wagner - University of North Carolina at Chapel HillVance G Fowler Jr - Duke University School of MedicineSarah E Rowe - Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27559Thomas Kehl-Fie - University of IowaBrian P Conlon - University of North Carolina at Chapel Hill
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.123(3), e2513462123
- DOI
- 10.1073/pnas.2513462123
- PMID
- 41533443
- PMCID
- PMC12818397
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 1091-6490
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Grant note
- R01AI173004 / HHS | NIH | NIAID | Division of Microbiology and Infectious Diseases (DMID) R21AI159369 / HHS | NIH | NIAID | Division of Microbiology and Infectious Diseases (DMID) R01AI179695 / HHS | NIH | NIAID | Division of Microbiology and Infectious Diseases (DMID) F30AI169746 / HHS | NIH | NIAID | Division of Microbiology and Infectious Diseases (DMID)
- Language
- English
- Date published
- 01/20/2026
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9985121588602771
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