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
Identifer | oai:union.ndltd.org:MIT/oai:dspace.mit.edu:1721.1/132987 |
Date | January 2018 |
Creators | Mourtada, Rida. |
Contributors | Harvard--MIT Program in Health Sciences and Technology., Harvard University--MIT Division of Health Sciences and Technology |
Publisher | Massachusetts Institute of Technology |
Source Sets | M.I.T. Theses and Dissertation |
Language | English |
Detected Language | English |
Type | Thesis |
Format | 189 pages, application/pdf |
Rights | MIT theses may be protected by copyright. Please reuse MIT thesis content according to the MIT Libraries Permissions Policy, which is available through the URL provided., http://dspace.mit.edu/handle/1721.1/7582 |
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