Developing Treatments for Methicillin-Resistant Staphylococcus Aureus Biofilms: Therapeutics and Drug Delivery

Deusenbery, Carly B.

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Year:: 2023
Contributor:: Deusenbery, Carly B (creator); Shukla, Anita (Advisor); Kizer, Megan (Reader); Wong, Ian (Reader); Mathiowitz, Edith (Reader); Brown University. School of Engineering (sponsor)
Genre:: theses
Subject:: Drug delivery systems; Polymeric drug delivery systems; Staphylococcus aureus; Antibiotics; MRSA; combination therapy; Antibacterial; Antibiofilm activity; Bacterial biofilms; Micelles
Extent:: xxi, 247 p.

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Abstract:: Biofilm formation and drug resistance complicate the treatment of bacterial infections. These infections are comprised of bacteria with low metabolic activity, limiting the effects of many antibiotics and diverse extracellular polymeric substances (EPS). The diversity of the EPS facilitates numerous ionic and hydrogen bonds producing a slime-like matrix. These EPS matrices create a physical barrier to disseminating therapeutics and to immune cells. These challenges in the treatment of biofilms result in billions of dollars in healthcare costs. Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most abundant opportunistic pathogens in the human microbiome that form biofilms and cause infections. The primary objectives of this thesis were to 1) develop a combination therapy to eradicate MRSA biofilms and to 2) develop a drug delivery system to enhance the delivery of therapeutics to eradicate MRSA biofilms. In order to prevent recurrence biofilm eradication re-lies on therapeutic activity against bacteria embedded in the biofilm, bacteria released from biofilm, in addition to the matrix itself. Combination therapies take advantage of the diverse mechanisms of antimicrobial therapeutics to enable synergistic mechanisms of action that can overcome drug resistance. Our studies demonstrate synergy between antibiofilm agents and antibiotics against MRSA biofilms. In this work, we evaluated bacterial colony burden, biofilm metabolic activity, cell membrane integrity, biovolume and matrix morphology to interpret the activity of therapeutic combinations. These studies emphasize the importance of complementary experiments to fully evaluate synergy and provide insight into the mechanisms of action. To develop a drug delivery system we synthesized an amphiphilic block copolymer using atom transfer radical polymerization. The synthesized block copolymer was then used to form micelles and encapsulate the antibiotic ciprofloxacin. We showed that under acidic conditions, matching the pH of developing MRSA biofilms, micelles swelled and released the loaded antibiotic. Ciprofloxacin-loaded micelles were found have enhanced activity against MRSA biofilm bacteria and biofilm supernatant bacteria com-pared to ciprofloxacin alone. Overall, the therapeutic strategies described here provide insight into the development of effective treatment for MRSA biofilms.
Notes:: Thesis (Ph. D.)--Brown University, 2023

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Citation

Deusenbery, Carly B., "Developing Treatments for Methicillin-Resistant Staphylococcus Aureus Biofilms: Therapeutics and Drug Delivery" (2023). Engineering Theses and Dissertations. Brown Digital Repository. Brown University Library. https://repository.library.brown.edu/studio/item/bdr:mh53e4nb/

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Engineering Theses and Dissertations

Theses and Dissertations for the Engineering department.
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