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Updated: Jul 15, 2025
A Tandem Liquid Chromatography–Mass Spectrometry-based Approach for Metabolite Analysis of Staphylococcus aureus
Published on: March 28, 2017
Inflammasome-mediated glucose limitation induces antibiotic tolerance in Staphylococcus aureus
Jenna E Beam1, Nikki J Wagner1, Kuan-Yi Lu1
1Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Abstract:
Staphylococcus aureus is a leading human pathogen that frequently causes relapsing infections. The failure of antibiotics to eradicate infection contributes to infection relapse. Host-pathogen interactions have a substantial impact on antibiotic susceptibility and the formation of antibiotic tolerant cells. In this study, we interrogate how a major S. aureus virulence factor, α-toxin, interacts with macrophages to alter the microenvironment of the pathogen, thereby influencing its susceptibility to antibiotics. We find α-toxin-mediated activation of the NLRP3 inflammasome induces antibiotic tolerance. Induction of tolerance is driven by increased glycolysis in the host cells, resulting in glucose limitation and ATP depletion in S. aureus. Additionally, inhibition of NLRP3 activation improves antibiotic efficacy in vitro and in vivo, suggesting that this strategy has potential as a host-directed therapeutic to improve outcomes. Our findings identify interactions between S. aureus and the host that result in metabolic crosstalk that can determine the outcome of antimicrobial therapy.
Insights
Staphylococcus aureus alpha-toxin triggers host NLRP3 inflammasome activation, leading to antibiotic tolerance in bacteria. Inhibiting this pathway enhances antibiotic effectiveness against infections.
Area of Science:
- Microbiology
- Immunology
- Infectious Diseases
Background:
- Staphylococcus aureus is a major cause of recurrent human infections.
- Antibiotic failure contributes to persistent infections and relapse.
- Host-pathogen interactions significantly influence antibiotic tolerance.
Purpose of the Study:
- To investigate how Staphylococcus aureus alpha-toxin affects host cells and bacterial antibiotic susceptibility.
- To determine the role of NLRP3 inflammasome activation in alpha-toxin-induced antibiotic tolerance.
- To explore the potential of targeting host-pathogen metabolic crosstalk for improved antimicrobial therapy.
Main Methods:
- Studied the interaction between S. aureus alpha-toxin and macrophages.
- Analyzed the impact of alpha-toxin on host cell metabolism (glycolysis).
- Assessed the effect of NLRP3 inflammasome activation on S. aureus antibiotic tolerance in vitro and in vivo.
Main Results:
- Alpha-toxin activates the NLRP3 inflammasome in macrophages.
- NLRP3 activation leads to increased host cell glycolysis, causing glucose depletion and ATP reduction in S. aureus.
- Inhibition of NLRP3 inflammasome activation enhances antibiotic efficacy against S. aureus.
Conclusions:
- Host-pathogen metabolic crosstalk, specifically alpha-toxin-mediated NLRP3 activation, drives antibiotic tolerance.
- Targeting the NLRP3 inflammasome represents a potential host-directed therapeutic strategy to overcome S. aureus antibiotic tolerance.
- Understanding these interactions is crucial for developing effective treatments for relapsing S. aureus infections.
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