Dissertation
REVITALIZING ANTIBIOTICS USING ANTIMICROBIAL PEPTIDES IN THE AGE OF MULTIDRUG RESISTANCE
Doctor of Philosophy (PhD), Washington State University
01/2020
Handle:
https://hdl.handle.net/2376/112092
Abstract
Multidrug-resistant bacteria are a growing global concern, and with increasingly prevalent resistance to last line antibiotics such as colistin, it is imperative that alternative treatment options are identified. Colistin normally binds to the lipid A moiety on the bacterial outer membrane where it then destroys the bacterial membrane. MCR (encoded by mcr-1 and others) is a phosphoethanolamine-transferase that modifies lipid A, thereby preventing colistin from binding. We hypothesized that combining pore-forming antimicrobial peptides and colistin will circumvent this mechanism and reduce the minimum-inhibitory concentration (MIC) of colistin for both colistin- and multidrug-resistant Gram-negative bacteria. Herein we investigated the mechanism of action and/or the combinatorial effectiveness of novel antimicrobial peptides (CDP-B03, CDP-B11 and CDP-C01), and previously characterized peptides, (MSI-78, OTD-195, and OTD-244) alone or with colistin against colistin- and multidrug-resistant Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Both MSI-78 and OTD-244 are known to kill bacteria by interacting with the bacterial membrane. Bacterial membrane-potential and membrane integrity assays, measured by flow cytometry, demonstrated that CDP-B11 disrupts the outer membrane of E. coli #0346. It is suspected that the mechanism of action for most antimicrobial peptides is by interacting with the bacterial membrane in some way, such as destroying the membrane by creating pores. Peptides MSI-78 and OTD-195 were effective in killing bacteria alone. All peptides except OTD-195 (tested against E. coli #0346 only) were able to lower the effective killing concentration of colistin to by greater than 4-fold against the bacteria tested. Importantly, no significant red blood hemolysis was observed for all peptides tested here either alone or in combination with colistin. The characteristics of the antimicrobial peptides presented here indicate that they could be used as a potential monotherapy or as combination therapy with colistin for the treatment of multidrug-resistant infections, including colistin-resistant infections.
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Details
- Title
- REVITALIZING ANTIBIOTICS USING ANTIMICROBIAL PEPTIDES IN THE AGE OF MULTIDRUG RESISTANCE
- Creators
- Kaitlin Witherell
- Contributors
- Douglas Call (Advisor)Anders Omsland (Committee Member)Troy Bankhead (Committee Member)Michael Konkel (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Veterinary Medicine, College of
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 73
- Identifiers
- 99900581701201842
- Language
- English
- Resource Type
- Dissertation