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Published on: May 13, 2017
The innate immune protein calprotectin ablates the bactericidal activity of β-lactam antibiotics
Amanda Z Velez1, Jana N Radin2, Emily N Kennedy1
1Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27559.
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.
Insights
Host protein calprotectin (CP) causes antibiotic tolerance by binding zinc, inactivating essential bacterial enzymes. This immune mechanism impairs β-lactam effectiveness during infections, highlighting zinc
Area of Science:
- Microbiology
- Immunology
- Pharmacology
Background:
- β-lactam antibiotics are crucial for treating bacterial infections.
- Therapeutic failures occur despite absence of genetic resistance.
- Host factors influencing antibiotic efficacy require further investigation.
Purpose of the Study:
- To identify host-derived mechanisms contributing to antibiotic tolerance.
- To elucidate the role of calprotectin (CP) in modulating β-lactam antibiotic efficacy.
- To understand how zinc availability impacts antibiotic treatment outcomes.
Main Methods:
- Investigated the effect of calprotectin (CP) on *Staphylococcus aureus* in vitro.
- Performed mechanistic studies on CP's interaction with bacterial autolysins.
- Assessed oxacillin efficacy in a murine infection model using CP-deficient mice.
Main Results:
- CP induces tolerance to β-lactam antibiotics by chelating zinc and inactivating autolysins.
- CP specifically inhibits the zinc-dependent autolytic activity of *S. aureus* Atl.
- Oxacillin efficacy was significantly enhanced in CP-deficient mice, demonstrating in vivo impairment by CP.
Conclusions:
- Calprotectin (CP) mediates a novel form of immune-driven antibiotic tolerance via zinc sequestration.
- Zinc availability at infection sites is critical for β-lactam antibiotic efficacy.
- Targeting host metal sequestration may offer strategies to improve antibiotic treatment outcomes.
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