UBC Theses and Dissertations
Investigating the structure-function relationship of cationic antimicrobial peptides and lipopeptides Cheng, John Tien Jui
Antibiotics have been playing a major role in combating bacterial infections for centuries. Since the discovery of modern antibiotics, numerous derivatives have been designed and developed to treat different bacterial infections. Recently, antibiotic resistance has been continuously and increasingly reported. The lack of antibiotic alternatives makes these resistant bacteria become more difficult to eliminate. Antimicrobial peptides constitute a major part of the innate immune system of an organism. Their high activity and little resistance make them ideal candidates for novel antibiotic development. This dissertation focuses on aurein peptides, a class of amphibian cationic antimicrobial peptides from Litoria aurea, and daptomycin, a lipopeptide. We have examined the structure-function relationship of two aurein peptides, aurein 2.2 and aurein 2.3. They were found to adopt alpha-helices and perturb membrane bilayers via mechanisms similar to toroidal pore or toroidal pore/liposome formation in model membranes. We have also designed and inspected the structure-activity correlation of different aurein 2.2 analogues by residue 13-substitutions and N- and/or C-terminal truncations. We have found that residue 13 and N-terminus are required for antimicrobial activity, whereas an N-terminal truncation gives rise to a peptide analogue with immunomodulatory activity in vitro. The effects of membrane composition and model membrane choice have been further investigated. We have found that the peptide behaviour is dependent on different model membranes. We have examined the importance of solvent accessibility in the mechanism of action for daptomycin and found that daptomycin molecules are indeed solvent-exposed in apo- and Ca2+-form and insert slightly into lipid membranes. Taken together, we have developed a set of references for future design of new antibiotics based on aurein peptides. By using this set of references as a starting point, we hope to gain a better understanding of how antimicrobial peptides function from structural and membrane perspectives and design novel antimicrobial agents to combat increasing antibiotic resistance in the future.
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