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MEMP - Thesis Defense - Rida Mourtada

Thursday, April 12, 2018 -- 9:00 AM

Smith Building RM 308-309
Dana-Farber Cancer Institute, Boston

Engineering Membrane-Selective Peptide Antibiotics to Combat Multidrug Resistance
 
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.  
 

In this thesis work, we subjected expansive stapled-peptide libraries of the Magainin-2 (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, roteolytically-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. We harnessed our new mechanistic insights into the selectivity and mode of membrane lysis to develop an algorithm for the design of a new generation of non-toxic, bacterial-selective StAMPs for clinical development.


Thesis Supervisor:
Loren D. Walensky, MD, PhD
Professor of Pediatrics, HMS

Thesis Committee Chair:
Matthew D. Shoulders, PhD 
Whitehead CD Associate Professor, MIT

Thesis Readers:
David E. Fisher, MD, PhD
Edward Wigglesworth Professor & Chairman of Dermatology, HMS

Deborah T. Hung, MD, PhD 
Associate Professor of Microbiology and Immunobiology, HMS

 
Date and Time: 
Thursday, April 12, 2018 - 9:00am to 11:00am
Location: 
Smith Building RM 308-309
Dana-Farber Cancer Institute, Boston