The innate immune protein calprotectin ablates the bactericidal activity of β-lactam antibiotics

Amanda Z Velez; Jana N Radin; Emily N Kennedy; Joshua B Parsons; Heather M Tong; Emma Jung; Emily Alam; Lauren C Radlinski; Nikki J Wagner; Vance G Fowler Jr; Sarah E Rowe; Thomas Kehl-Fie; Brian P Conlon

doi:10.1073/pnas.2513462123

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The innate immune protein calprotectin ablates the bactericidal activity of β-lactam antibiotics

Journal article

Open access

Peer reviewed

The innate immune protein calprotectin ablates the bactericidal activity of β-lactam antibiotics

Amanda Z Velez, Jana N Radin, Emily N Kennedy, Joshua B Parsons, Heather M Tong, Emma Jung, Emily Alam, Lauren C Radlinski, Nikki J Wagner, Vance G Fowler Jr, …

Proceedings of the National Academy of Sciences - PNAS, Vol.123(3), e2513462123

01/20/2026

DOI: 10.1073/pnas.2513462123

PMCID: PMC12818397

PMID: 41533443

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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.

Animals

Anti-Bacterial Agents - pharmacology

beta Lactam Antibiotics

beta-Lactams - pharmacology

Humans

Immunity, Innate

Leukocyte L1 Antigen Complex - genetics

Leukocyte L1 Antigen Complex - immunology

Leukocyte L1 Antigen Complex - metabolism

Mice

Mice, Inbred C57BL

N-Acetylmuramoyl-L-alanine Amidase - antagonists & inhibitors

N-Acetylmuramoyl-L-alanine Amidase - metabolism

Neutrophils - immunology

Neutrophils - metabolism

Oxacillin - pharmacology

Staphylococcal Infections - drug therapy

Staphylococcal Infections - immunology

Staphylococcal Infections - microbiology

Staphylococcus aureus - drug effects

Staphylococcus aureus - immunology

Zinc - metabolism

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 Hill
Jana N Radin - University of Iowa
Emily N Kennedy - University of North Carolina at Chapel Hill
Joshua B Parsons - Duke University
Heather M Tong - University of North Carolina at Chapel Hill
Emma Jung - University of North Carolina at Chapel Hill
Emily Alam - University of North Carolina at Chapel Hill
Lauren C Radlinski - University of California, Davis
Nikki J Wagner - University of North Carolina at Chapel Hill
Vance G Fowler Jr - Duke University School of Medicine
Sarah E Rowe - University of North Carolina at Chapel Hill
Thomas Kehl-Fie - University of Iowa
Brian 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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