טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentPorat Yaara
SubjectAntimicrobial Peptides and Peptidomimetics for
Controlling Oral Microflora
DepartmentDepartment of Biotechnology and Food Engineering
Supervisor Professor Amram Mor


Abstract

Antimicrobial peptides (AMPs) represent a promising group of new therapeutic agents, thanks to their rapid effect, large activity spectrum and lack of microbial resistance. Previous structure activity relationship studies in the amphibian AMP dermaseptin derivative S4(1-15) have shown that replacement of N-terminus amino acid(s) with various fatty acids resulted in potency recovery or improvement, through modulating the peptide’s hydrophobicity and/or charge. This study further examined the effect of acyl substitution over antimicrobial activity of dermaseptin S4(1-15) derivatives, and of peptide-like compounds, using similar methods, towards potential topical application such as in the case of oral infections. The substituted derivative C7-S4(3-15), showed improved antibacterial properties, which correlated to changes in the peptides secondary structure. C7-S4(3-15) and another potent substituted analog, NC12-S4(3-15) were bactericidal to oral pathogens immobilized in a biofilm. When tested for their activity against oral microflora in human saliva, the derivatives preformed similarly to IB-367, a peptide assessed in clinical trials for treatment of oral mucositis.

            Recent work in the lab led to the design of a library of antimicrobial peptidomimetics based on acyl and lysine copolymers (termed OAKs), representing the two most important characteristics for AMPs activity (i.e., hydrophobicity & charge). This study further optimized OAKs properties by the production of new library members, termed β-OAKs, characterized by introduction of a tandem-lysine motif into the oligomer sequence. This was shown to inhibit self assembly and consequently improve antibacterial potency while increasing molecular susceptibility to proteolysis compared with equivalent original OAKs. Truncation and acylation of β-OAKs provided shorter derivatives with improved antibacterial spectrum of activity that exhibited bactericidal properties in culture medium as well as in saliva, pointing to β-OAKs potential for controlling oral pathogens.

            Collectively, the data gathered in this work indicate that acyl substitutions are a useful strategy in developing potent derivatives of AMPs as well as OAKs for controlling oral microflora. Moreover, this study reinforces the conjecture that OAKs represent a suitable yet simple model for studying the effect of hydrophobicity and charge over antimicrobial activity in AMPs.