Engineering membrane-selective antibiotic peptides to combat multidrug resistance

Thesis: Ph. D. in Medical Engineering and Medical Physics, Harvard-MIT Program in Health Sciences and Technology, June, 2018Cataloged 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 PhysicsPh.D.inMedicalEngineeringandMedicalPhysics Harvard-MIT Program in Health Sciences and Technolog

A Journey down the Cell Death Pathway of Mitochondria-targeted Chlorambucil

Our lab recently demonstrated that retargeting an alkylating agent, chlorambucil (Cbl), to the mitochondrion is a viable strategy to restore drug activity and overcome drug resistance in cancer. The mechanism of action of the mitochondria-targeted chlorambucil (mt-Cbl) was studied using a cervical carcinoma model. It was discovered that mt-Cbl bound to mitochondrial DNA and various mitochondrial proteins. A ρ° model revealed that the toxicity of mt-Cbl is largely dependent on its protein targets. Damage induced by mt-Cbl was found to result in the activation of several modes of caspase-independent cell death including necrosis. In contrast, Cbl was found to only activate caspase-dependent cell death that is highly sensitive to caspase inhibition. These results illustrate that the ability of mt-Cbl to activate various orthogonal cell death pathways is what allows mt-Cbl to bypass several drug resistance mechanisms, thus making mitochondrial retargeting a lucrative strategy for future anticancer drug development.MAS

Maquam al-Sayedah Zeinab

interior, tiled archways, 199

Sayyida Zaynab Mosque

exterior, southeastern corner of courtyard, with minaret, October 200

Sayyida Zaynab Mosque

exterior, partial view of facade and dome, October 200

Sayyida Zaynab Mosque

exterior, dome, October 200

Sayyida Zaynab Mosque

exterior, dome, October 200

Maquam al-Sayedah Zeinab

detail, doors, 199

Maquam al-Sayedah Zeinab

interior, view through archway to courtyard, with dome under restoration, 199

Legislative Documents

Also, variously referred to as: House bills; House documents; House legislative documents; legislative documents; General Court documents