Using a liver-on-chip model to evaluate the effects of vancomycin and daptomycin on host immunometabolism and clearance of intracellular reservoirs of Staphylococcus aureus during bacteremia
4 affiliations
- 1Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, California, USA
- 2Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
- 3Board of Governors Regenerative Medicine Institute, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California, USA
- 4Department of Pharmacy, Huntington Health, Pasadena, California, USA
Abstract
Staphylococcus aureus bacteremia (SAB) causes significant morbidity and mortality, despite treatment with guideline-recommended antibiotics. A critical contributor to SAB treatment failure is the intracellular persistence of SA within liver sinusoidal macrophages (Kupffer cells [KCs]). Antibiotics have been shown to modulate immune cell function, which is governed by cellular metabolism; yet, the effect of antibiotics on host immunometabolic response relative to bacterial clearance is understudied. We developed a liver-on-chip (LoC) model of SAB to recapitulate the liver sinusoid during systemic infection using exclusively liver-derived cells and the GFP USA300 LAC SA strain and compared the effects of vancomycin and daptomycin on host immunometabolism by fluorescence lifetime imaging microscopy and related to intracellular antimicrobial efficacy. Utilizing both murine and human-based LoC infection models, we found that DAP was superior to VAN treatment in clearing intracellular SA from the liver microenvironment, which corresponded to differential host immunometabolic responses. DAP showed low NAD(P)H fluorescence lifetime and low mitochondrial ROS, suggestive of a redox-buffered state that balanced pathogen containment with hepatic metabolic homeostasis, while VAN treatment biased towards greater utilization of OXPHOS. Our findings using a novel in vitro microphysiological system mimicking the liver tissue microenvironment offer insights into antibiotic-mediated bacterial clearance that accounts for host immunometabolism beyond direct antimicrobial activity.
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BibTeX
@article{beadell2026using,
title = {{Using a liver-on-chip model to evaluate the effects of vancomycin and daptomycin on host immunometabolism and clearance of intracellular reservoirs of Staphylococcus aureus during bacteremia}},
author = {Brent Beadell and Sujung Yi and Makayla Roberts and Kyu Shik Mun and Annie Wong-Beringer},
journal = {Antimicrobial Agents and Chemotherapy},
year = {2026},
month = jul,
doi = {10.1128/aac.00254-26},
url = {https://doi.org/10.1128/aac.00254-26},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Using a liver-on-chip model to evaluate the effects of vancomycin and daptomycin on host immunometabolism and clearance of intracellular reservoirs of Staphylococcus aureus during bacteremia
AU - Brent Beadell
AU - Sujung Yi
AU - Makayla Roberts
AU - Kyu Shik Mun
AU - Annie Wong-Beringer
PY - 2026
DA - 2026/07/23
JO - Antimicrobial Agents and Chemotherapy
DO - 10.1128/aac.00254-26
UR - https://doi.org/10.1128/aac.00254-26
AB - Staphylococcus aureus bacteremia (SAB) causes significant morbidity and mortality, despite treatment with guideline-recommended antibiotics. A critical contributor to SAB treatment failure is the intracellular persistence of SA within liver sinusoidal macrophages (Kupffer cells [KCs]). Antibiotics have been shown to modulate immune cell function, which is governed by cellular metabolism; yet, the effect of antibiotics on host immunometabolic response relative to bacterial clearance is understudied. We developed a liver-on-chip (LoC) model of SAB to recapitulate the liver sinusoid during systemic infection using exclusively liver-derived cells and the GFP USA300 LAC SA strain and compared the effects of vancomycin and daptomycin on host immunometabolism by fluorescence lifetime imaging microscopy and related to intracellular antimicrobial efficacy. Utilizing both murine and human-based LoC infection models, we found that DAP was superior to VAN treatment in clearing intracellular SA from the liver microenvironment, which corresponded to differential host immunometabolic responses. DAP showed low NAD(P)H fluorescence lifetime and low mitochondrial ROS, suggestive of a redox-buffered state that balanced pathogen containment with hepatic metabolic homeostasis, while VAN treatment biased towards greater utilization of OXPHOS. Our findings using a novel in vitro microphysiological system mimicking the liver tissue microenvironment offer insights into antibiotic-mediated bacterial clearance that accounts for host immunometabolism beyond direct antimicrobial activity.
SN - 0066-4804
SN - 1098-6596
ER -