Mechanistic studies and biomedical applications of antimicrobial peptoids against multi-drug resistant bacterial infections
Abstract/Contents
- Abstract
- The increasing prevalence of chronic, difficult-to-treat resistant bacterial infections have created a pressing need for the discovery of promising, novel pharmaceutical candidates that could replace or complement current therapies, which are becoming less reliable and effective due to a rise in bacterial resistance. Antimicrobial peptides (AMPs) are a naturally occurring, ubiquitous, and ancient class of antibiotics that offer a unique template for the development of novel antimicrobial therapies. However, in vivo therapeutic peptides have a short half-life since they are easily degraded by proteases, thus reducing their bioavailability, which renders them a less attractive choice therapeutically. Consequently, non-natural mimics of AMPs, which can emulate the favorable characteristics of AMPs are becoming significantly important. Poly-N-substituted glycines, also called "Peptoids", are structural and functional mimics of AMPs and are resistant to proteolysis. Predecessors in the Barron laboratory designed and characterized antimicrobial peptoids against free-floating, planktonic bacteria. However, almost 60% of infections are caused by bacterial biofilms. These complex communities of microorganisms are protected by an excreted matrix of adhesive biomacromolecules and are more difficult to kill with conventional antibiotics than planktonic bacteria. Furthermore, to develop peptoids as potential therapeutics, the mechanisms by which they interact with bacteria need to be understood, which are still under investigation. Here, we report that peptoids have similar or better efficacy than conventional antibiotics against biofilms of a clinical isolate of drug-resistant P. aeruginosa. We determined the effects of peptoids on bacterial biomass and cell viability, by Crystal Violet assay and bacterial plating, respectively. We also explored the efficacy of peptoids against Mycobacterium (an organism resistant to antibiotics due to the presence of a thick waxy coating) and intracellular L. monocytogenes by bioluminescent imaging. In addition, we also investigated the mechanisms of action of peptoids and peptides by biophysical techniques (Ultra-Violet Visible spectroscopy) and bioluminescent imaging. We report that peptoids are non-lytic and cause bacterial killing by aggregating the bacterial ribosomes and decreasing ATP levels inside the cell. Lastly, we present a mouse wound model, which suggests that peptoids are effective in vivo in reducing P. aeruginosa infections.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2011 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Kapoor, Rinki |
|---|---|
| Associated with | Stanford University, Biophysics Program. |
| Primary advisor | Barron, Annelise E |
| Thesis advisor | Barron, Annelise E |
| Thesis advisor | Contag, Christopher H |
| Thesis advisor | Swartz, James R |
| Advisor | Contag, Christopher H |
| Advisor | Swartz, James R |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Rinki Kapoor. |
|---|---|
| Note | Submitted to the Biophysics Program. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2011. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2011 by Rinki Kapoor
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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