Mandell, Jonathan
(2023)
STAPHYLOCOCCUS AUREUS BIOFILMS: TOXIN ANTITOXIN MazEF REGULATION OF CHRONIC INFECTIONS AND NOVEL ANTIMICROBIAL TREATMENTS.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Biomedical implant infections account for ~25% of all hospital associated infections and are often refractory to antibiotic treatments. These infections are difficult to clear as they are primarily caused by Staphylococcus aureus which establishes mature biofilms on the implant material and surrounding tissue. These characteristics of S. aureus biofilms are largely recognized as the cause of these often chronic and difficult to treat infections. In this work, I evaluated the contribution of the MazEF toxin antitoxin system in S. aureus biofilm formation, antibiotic tolerance, and in vivo mouse bacteremia, abscess, and biomedical implant infection models. Additionally, I tested the ability of the novel antimicrobial peptide PLG0206 to kill multidrug resistant pathogen biofilms in vitro and clear S. aureus biofilms using a rabbit periprosthetic joint infection (PJI) model. mazF::tn displayed significantly increased cell division when grown as planktonic cultures and increased biofilm growth on metal implant material compared to WT and mazF::tn + complement. Using a mouse PJI model, mazF::tn displayed increased biofilm burden in the acute phase of the infection and decreased biofilm burden during the chronic phase of the infection compared to WT. In vitro, mazF::tn displayed sensitivity to the beta lactam antibiotic cefazolin compared to resistance displayed in WT. In vivo, mazF::tn bacteremia in mice was effectively treated using cefazolin while WT bacteremia resulted in 80% mortality. PLG0206 dissolved in pH adjusted PBS was able to reduce over 99.9% of multidrug resistant ESKAPE pathogen biofilms in under 15 minutes compared to vehicle alone. Additionally in rabbits, PLG0206 statistically reduced S. aureus biofilms when used intraoperatively during an irrigation and debridement (I&D) of the infected implant and surrounding tissue compared to I&D alone. Rabbits which received intraoperative PLG0206 treatment along with systemic cefazolin resulted in significantly increased survival compared to I&D alone and cefazolin monotreatment groups. Improved understanding of S. aureus biofilm phenotypes will lead to novel strategies to both prevent and treat S. aureus biofilms and improve public health by reducing substantial morbidity and mortality of hospital patients.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
3 January 2023 |
| Date Type: |
Publication |
| Defense Date: |
30 November 2022 |
| Approval Date: |
3 January 2023 |
| Submission Date: |
15 December 2022 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
142 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Infectious Diseases and Microbiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
N.A. |
| Date Deposited: |
03 Jan 2023 15:28 |
| Last Modified: |
03 Jan 2023 15:28 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/44031 |
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