|Ph.D Student||Radzishevsky Inna|
|Subject||Oligo Acyl-Q (OAQ): Novel Antimicrobial Pseudo-Peptides|
Based on Fatty Acids and Positively Charged
|Department||Department of Biotechnology||Supervisor||Professor Amram Mor|
|Full Thesis text|
Gene-encoded antimicrobial peptides (AMPs) are important ubiquitous component of host defense. They represent a promising alternative in fighting the emergence and worldwide spread of multidrug-resistant bacteria. AMPs do not target specific microbial receptors generally, but rather assume amphipathic secondary structures believed to allow them to interact non-specifically with various microbial targets and ultimately lead to rapid cell death. Such antimicrobial compounds present incontestable advantages over conventional antibiotics but also several disadvantages such as high toxicity due to their non-specific mode of action and other disadvantages inherent to peptides as drugs in general (e.g., poor bioavailability and high production cost).
My research therefore focused on addressing some of these issues through the study of novel backbone-flexible peptide-mimetics termed oligo-acyl-lysines (OAKs). A library of OAKs was produced by forthright solid-phase peptide synthesis and screened for promising properties then selected OAKs were further characterized by physical, chemical and biological methods aiming to reveal molecular elements responsible for potent and/or selective antimicrobial activity.
A quantitative structure-activity relationship study based on 103 OAKs indicated that potent antibacterial activity requires a relatively narrow (possibly specific) window of hydrophobicity-charge values where the acyl length plays multiple and critical roles both in molecular organization and selective activity. Thus, incorporation of long - but not short - acyl chains within a peptide backbone can lead to rigid supra-molecular organization responsible for poor antibacterial activity and enhanced hemolytic activity. However, sequence manipulations that included introduction of a tandem-lysine motif into the oligomer backbone enabled disassembly of aggregated OAKs.
Specific octanoyl-based OAKs showed rapid, broad-spectrum bactericidal properties in mice and did not induce emergence of resistance under conditions of selective pressure. These OAKs combined high plasma stability with extremely low hemolytic activity and a pronounced lack of secondary structure.
Some of these OAKs also displayed selective activity against the intra-erythocytes malaria parasite, Plasmodium falciparum suggesting that non-hemolytic OAKs may act through selective membrane disruption of the intra-erythrocytic parasite.
Collectively, the data seem to refute the dogma that ties AMPs activity to stable secondary structures and point to OAKs design as a convenient platform to study and develop low-toxicity compounds with potential for treatment of microbial infections and other biomedical applications.