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Published on: May 15, 2019
Saturated fatty acids enhance daptomycin activity in a Fak-dependent manner in enterococci
Sudan Maharjan1, Troy A Getty1, Quiana Dickens1
1Department of Microbiology, University of Tennessee, Knoxville, Tennessee, USA.
Abstract:
Antibiotic resistance of Gram-positive bacteria poses a major clinical challenge. Daptomycin, a lipopeptide antibiotic, is a treatment option for drug-resistant organisms. However, there have been clinical reports of daptomycin resistance and in vitro reports of daptomycin tolerance that can result in treatment failure. Daptomycin possesses a fatty acid tail that inserts into the membrane, and membrane fatty acid content can influence its binding. Given that, we examined the potential of fatty acids to enhance daptomycin activity against enterococcal strains. We demonstrate that the saturated fatty acids myristic and palmitic acids increase bacterial susceptibility to the antibiotic, even for a daptomycin-resistant clinical isolate. These effects were highly specific with no impact on daptomycin susceptibility of Staphylococcus aureus. Growth of enterococci with myristic or palmitic acid reduced membrane fluidity, potentially promoting tighter daptomycin insertion. However, we noted no difference in membrane permeability for cells treated with fatty acids and daptomycin. While cells exposed to saturated fatty acids experience greater membrane depolarization, the lack of consistent, significant time-dependent changes upon daptomycin treatment suggests that depolarization alone does not fully explain the increased sensitivity. A strain that is unable to incorporate exogenous fatty acids into phospholipids was insensitive to the effects of saturated fatty acids on its susceptibility to daptomycin, highlighting the necessity of fatty acid incorporation onto lipid headgroups for potentiation. Overall, our data suggest that the incorporation of specific saturated fatty acids within the enterococcal membrane likely disrupts lipid composition, membrane organization and cellular envelope homeostasis, ultimately contributing to enhanced daptomycin susceptibility.
Insights
Adding saturated fatty acids like myristic and palmitic acid enhances daptomycin antibiotic effectiveness against resistant enterococci. This strategy improves bacterial susceptibility by altering membrane composition.
Area of Science:
- Microbiology
- Molecular Biology
- Drug Discovery
Background:
- Antibiotic resistance in Gram-positive bacteria, including enterococci, presents a significant clinical challenge.
- Daptomycin is a crucial lipopeptide antibiotic for treating infections caused by drug-resistant Gram-positive pathogens.
- Emerging daptomycin resistance and tolerance in clinical settings necessitate strategies to restore antibiotic efficacy.
Purpose of the Study:
- To investigate the potential of exogenous saturated fatty acids to enhance daptomycin activity against enterococcal strains.
- To elucidate the mechanisms by which fatty acids modulate bacterial membrane properties and daptomycin susceptibility.
Main Methods:
- Treatment of enterococcal strains with daptomycin in combination with saturated fatty acids (myristic acid, palmitic acid).
- Assessment of bacterial susceptibility to daptomycin using various microbiological assays.
- Analysis of bacterial membrane properties, including fluidity, permeability, and depolarization.
- Genetic manipulation of enterococcal strains to assess the role of fatty acid incorporation into phospholipids.
Main Results:
- Myristic and palmitic acids significantly increased daptomycin susceptibility in enterococci, including a daptomycin-resistant isolate.
- These effects were specific to enterococci, with no observed impact on *Staphylococcus aureus* susceptibility.
- Fatty acid treatment reduced membrane fluidity and caused depolarization, but did not alter membrane permeability.
- The potentiation effect was dependent on the ability of the bacteria to incorporate exogenous fatty acids into their phospholipids.
Conclusions:
- Specific saturated fatty acids can restore daptomycin susceptibility in resistant enterococci by altering membrane lipid composition and organization.
- Fatty acid incorporation into phospholipids is essential for this observed potentiation effect.
- This approach offers a potential strategy to combat daptomycin resistance in enterococcal infections by modulating bacterial membrane homeostasis.
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