Harnessing Membrane-Acting Agents to Enhance Antibiotic Efficacy Against Staphylococcus aureus
Public Deposited- Creator
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Sidders, Ashelyn Elizabeth
- School of Medicine, Department of Microbiology and Immunology
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Sidders, Ashelyn Elizabeth
- Abstract
- Antibiotic tolerance and antibiotic resistance are the two major obstacles to the efficient and reliable treatment of bacterial infections. Unfortunately, novel antimicrobial development is unlikely to be the answer to mitigating treatment failure as there have only been two new classes of antibiotics introduced in nearly half a century. Moving forward, if we are to maintain the use of our current arsenal of antibiotics, we need to develop innovative approaches to tackle difficult-to-treat bacterial infections. Here we identified strategies that improve classic antibiotic treatment by: (I) identifying an antibiotic adjuvant that potentiates multiple antibiotics, and (II) improving the penetration of antibiotics into bacterial biofilms. We determined that palmitoleic acid, a mono-unsaturated fatty acid, is a potent antibiotic adjuvant for vancomycin, bacitracin, and aminoglycosides through different mechanisms. We show that palmitoleic acid enhances vancomycin and bacitracin activity through the rapid accumulation of membrane-bound cell wall intermediates that generate large fluid patches in the membrane leading to protein delocalization, aberrant septal formation, and loss of membrane integrity. In contrast, we find that palmitoleic acid potentiates aminoglycosides by increasing membrane permeability which facilitates increased drug uptake. Compared to antibiotic monotherapy, we find that combining these antibiotics with palmitoleic acid drastically improves the rate of killing and sensitizes both tolerant and resistant populations to antibiotic killing. Additionally, an infection niche that is notoriously tolerant to antibiotics, especially aminoglycosides, is bacterial biofilms. This is due to poor aminoglycoside uptake into tolerant cells and poor antibiotic penetration into the biofilm. Here, we utilize Sonobactericide, a non-invasive ultrasound-mediated drug delivery technology that improves penetration of therapeutics. By combining Sonobactericide and palmitoleic acid-aminoglycoside therapy we dramatically improve treatment efficacy against a methicillin-resistant Staphylococcus aureus wound infection in diabetic mice. Overall, the findings presented here suggest that palmitoleic acid is a multifaceted antibiotic adjuvant with significant clinical potential to improve the efficacy of existing FDA-approved drugs. Additionally, the mechanistic insight underlying synergy with palmitoleic acid can further be exploited to develop additional therapeutic options that improve treatment outcomes.
- Date of publication
- 2023
- Keyword
- DOI
- Resource type
- Rights statement
- In Copyright - Educational Use Permitted
- Advisor
- Conlon, Brian P
- Rowe, Sarah E
- Braunstein, Miriam
- Cotter, Peggy A
- Tamayo, Rita
- Nicholas, Robert A
- Degree
- Doctor of Philosophy
- Degree granting institution
- University of North Carolina at Chapel Hill Graduate School
- Graduation year
- 2023
- Language
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