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Loren D. Walensky. Mourtada, Rida. Harvard--MIT Program in Health Sciences and Technology. Harvard University--MIT Division of Health Sciences and Technology 2021-10-15T15:29:20Z 2021-10-15T15:29:20Z 2018 2018 https://hdl.handle.net/1721.1/132987 1263579513 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 189 pages eng Massachusetts Institute of Technology 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 Harvard--MIT Program in Health Sciences and Technology. Engineering membrane-selective antibiotic peptides to combat multidrug resistance Thesis application/pdf 2021-10-15T15:29:20Z Publication Doctoral HST unknown unknown <Publication xmlns="https://www.openaire.eu/cerif-profile/1.1/" id="aafb40ab-466c-44a1-a4d3-167f8c2c372b"> <Type xmlns="https://www.openaire.eu/cerif-profile/vocab/COAR_Publication_Types">http://purl.org/coar/resource_type/c_1843</Type> <Language>eng</Language> <Title>Engineering membrane-selective antibiotic peptides to combat multidrug resistance</Title> <PublishedIn> <Publication> </Publication> </PublishedIn> <PublicationDate>2018</PublicationDate> <Authors> <Author> <DisplayName>Mourtada, Rida.</DisplayName> <Affiliation> <OrgUnit> </OrgUnit> </Affiliation> </Author> </Authors> <Editors> </Editors> <Publishers> <Publisher> <DisplayName>Massachusetts Institute of Technology</DisplayName> <OrgUnit /> </Publisher> </Publishers> <License>http://dspace.mit.edu/handle/1721.1/7582</License> <Keyword>Harvard--MIT Program in Health Sciences and Technology.</Keyword> <Abstract>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.</Abstract> <Access xmlns="http://purl.org/coar/access_right" > </Access> </Publication>