Mandell, Jonathan
(2019)
Staphylococcus aureus biofilms are highly tolerant to traditional antibiotics but susceptible to engineered antimicrobial peptide WLBU2.
Master's Thesis, University of Pittsburgh.
(Unpublished)
Abstract
Hospital associated infection remains a major problem which is responsible for ~100,000 deaths and over 10 billion dollars in health care costs annually in the US alone. Peri-prosthetic joint infection of total knee arthroplasties is an extremely challenging hospital associated infection to treat. These infections are challenging to treat due to the presence of established S. aureus bacterial biofilms on implant material and surrounding tissue. S. aureus biofilms secrete an extensive extracellular matrix structure, have altered stress response abilities, and have an increased proportion of metabolically inert “persister” cells. Antimicrobial peptides have been widely considered as a new class of antibiotic which could assist in the dilemma of drug tolerance bacterial biofilms. Engineered cationic amphipathic peptide WLBU2 is a rationally designed antimicrobial peptide, which maximizes bacterial membrane attachment and disruption and decreases toxicity to mammalian cells. Here we hypothesize that S. aureus clinical isolate biofilms will display increased tolerance to clinically used antibiotics compared to planktonic cells in vitro. Additionally, we hypothesize that compared to cefazolin, WLBU2 has higher activity against S. aureus biofilms grown on implant material in vitro and can more effectively treat PJI in mice. We found that clinical isolates grown as biofilms were significantly more tolerant to all ten clinically administered antibiotics tested compared to the same isolates grown as planktonic cells. Only rifampin, doxycycline, and daptomycin displayed activity against most bacterial biofilms tested. WLBU2 could kill over 99.9% of S. aureus biofilms grown on metal implant pieces in under two hours, while cefazolin failed to achieve this anti-biofilm activity over 24 hours. Finally, we demonstrated WLBU2 could more effectively treat periprosthetic joint infection in mice than cefazolin. In terms of public health significance, understanding how to better kill and clear established bacterial biofilms utilizing novel antimicrobial peptides will be crucial in decreasing the extensive morbidity and mortality from hospital and community associated infections.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
| Title | Member | Email Address | Pitt Username | ORCID |
|---|
| Committee Chair | Urish, Kenneth | | | | | Committee Member | Mailliard, Robbie | | | | | Committee Member | Sluis-Cremer, Nicolas | | | |
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| Date: |
30 January 2019 |
| Date Type: |
Publication |
| Defense Date: |
5 December 2018 |
| Approval Date: |
30 January 2019 |
| Submission Date: |
26 November 2018 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
77 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Infectious Diseases and Microbiology |
| Degree: |
MS - Master of Science |
| Thesis Type: |
Master's Thesis |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
N/A |
| Date Deposited: |
30 Jan 2020 06:00 |
| Last Modified: |
01 Jan 2024 06:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/35603 |
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