Masters Theses
Date of Award
8-2025
Degree Type
Thesis
Degree Name
Master of Science
Major
Microbiology
Major Professor
Elizabeth M. Fozo
Committee Members
Todd Reynolds, Steven M. Abel
Abstract
Antimicrobial resistance (AMR) among Gram-positive pathogens, including enterococci, presents a significant clinical challenge. Daptomycin, a key lipopeptide antibiotic used against resistant infections, can lose efficacy due to bacterial adaptations, especially in response to host-derived factors. Notably, human serum exposure has been shown to induce daptomycin tolerance, although the precise mechanisms remain unclear. Serum exposure increases daptomycin MICs in enterococci and has strain-specific effects in Staphylococcus aureus, likely through host-derived lipid interactions. This study investigates the role of saturated fatty acids (SFAs) in modulating daptomycin susceptibility in enterococcal strains. We show that supplementation with SFAs (lauric, myristic, palmitic acids) potentiates daptomycin activity in enterococci, but not in S. aureus, suggesting species-specific mechanisms. Membrane analyses reveal that SFAs reduce membrane fluidity compared to controls, but fluidity paradoxically increases after daptomycin exposure, indicating membrane adaptation. Dual treatment with SFAs and daptomycin shifted membrane permeability and increased membrane depolarization, but these changes do not directly correlate with the potentiation of daptomycin. We propose that SFA-induced membrane changes create hyper-fluid microdomains that promote daptomycin insertion more effectively. Daptomycin’s interaction with phosphatidylglycerol (PG) may deplete PG-rich regions, leading to lipid redistribution and destabilizing the membrane. This likely disrupts membrane protein function, including that of essential enzymes, leading to structural and functional collapse of the cell and ultimately, cell death. These findings provide insight into the interplay between host-derived fatty acids and antibiotic susceptibility. They suggest that targeting membrane composition with SFAs may offer a potential strategy to enhance daptomycin efficacy and combat AMR.
Recommended Citation
Maharjan, Sudan, "Environmental fatty acid sources can alter the antibiotic susceptibility of Enterococci and other Gram-positive bacteria. " Master's Thesis, University of Tennessee, 2025.
https://trace.tennessee.edu/utk_gradthes/14547
Included in
Bacterial Infections and Mycoses Commons, Bacteriology Commons, Medical Microbiology Commons, Microbial Physiology Commons, Pathogenic Microbiology Commons