Engineering membrane-selective antibiotic peptides to combat multidrug resistance
| Autor: | Mourtada, Rida. |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: | |
| Druh dokumentu: | Diplomová práce |
| Popis: | Thesis: Ph. D. in Medical Engineering and Medical Physics, Harvard-MIT Program in Health Sciences and Technology, June, 2018 Cataloged from the official PDF version of thesis. Includes bibliographical references. Antibiotic resistance is a global health emergency that mandates new drug development strategies. Natural antimicrobial peptides (AMPs) have been long-recognized as a potential source of bacteriolytic drugs, but the shortcomings of non-specific membrane toxicity, proteolytic instability, and in vivo toxicity have stymied their clinical translation. Here, we subjected expansive stapled-peptide libraries of the magainin II (Mag2) AMP to structure-function analyses and uncovered the biophysical and mechanistic determinants that allow for the rational design of stapled AMPs (StAMPs) that are bacterial-membrane selective, proteolytically-stable, well tolerated in mice upon intravenous administration, and most importantly, overcome even the most antibiotic-resistant bacteria, including colistin-resistant A. baumannii and mobilized colistin resistance plasmid-bearing E. coli. Specifically, we discovered that the topographic continuity and strength of hydrophobic networks, in the context of alpha-helical amphipathic cationic peptides, dictates both the selectivity and mechanism of membrane lysis. We further harnessed our results to develop an algorithm for the design of a new generation of non-toxic, bacterial-selective StAMPs for clinical development. by Rida Mourtada. Ph. D. in Medical Engineering and Medical Physics Ph.D.inMedicalEngineeringandMedicalPhysics Harvard-MIT Program in Health Sciences and Technology |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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