Design and synthesis of cationic amphiphiles

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dc.contributor.authorFindlay, Brandon
dc.contributor.examiningcommitteeO'Neil, Joe (Chemistry) Sorensen, John (Chemistry) Chee, Lean (Pharmacy) Zhanel, George G. (Medical Microbiology) Kaur, Kamaljit (University of Alberta)en_US
dc.contributor.supervisorSchweizer, Frank (Chemistry)en_US
dc.date.accessioned2013-07-08T15:05:28Z
dc.date.available2013-07-08T15:05:28Z
dc.date.issued2010en_US
dc.date.issued2012en_US
dc.date.issued2013en_US
dc.date.issued2012en_US
dc.degree.disciplineChemistryen_US
dc.degree.levelDoctor of Philosophy (Ph.D.)en_US
dc.description.abstractCationic antimicrobial peptides (CAMPs) are produced by plants, animals and bacteria to protect their host against antagonistic microbes. The antitheses of selective antibiotics, these peptides are drawn by electrostatic and hydrophobic interactions to targets as diverse as the bacterial membrane, nucleic acids and serum proteins. This lack of specificity is their greatest strength, as mutations to single genes rarely lead to bacterial resistance. Resistance may be conferred by large scale alterations in cell envelope composition, which generally reduces bacterial fitness in the absence of peptide. Clinical applications of natural CAMPs are limited, as the peptides are toxic to mammalian cells and rapidly inactivated in vivo by serum albumin and proteases. Faced with these challenges we have prepared a number of CAMP analogues, with the goal of creating lead compounds for further development of antibacterial therapeutics. Much of our work has focused on ultrashort lipopeptides and lipopeptoids, which have properties similar to natural CAMPs and extremely abbreviated sequences. The simple structure of these scaffolds allows rapid creation of CAMP analogues in a brief period of time, allowing us to rapidly explore the structural requirements for CAMP activity. The balance of this work focuses on imparting CAMP-like behaviour to known antibiotics, in order to expand their spectrum of susceptible bacteria and combat the development of drug-resistant bacteria. In particular, the aminoglycosides neomycin and tobramycin have been fused to phenolic disinfectants such as triclosan and biclotymol, in order to improve their diffusion across the bacterial envelope and activity against Gram-negative bacteria.en_US
dc.description.noteOctober 2013en_US
dc.identifier.citationAntimicrobial Agents and Chemotherapy, 54, 2010, 4049-58. doi: 10.1128/AAC.00530-10.en_US
dc.identifier.citationInternational Journal of Antimicrobial Agents, 40, 2012, 36-42. doi: 10.1016/j.ijantimicag.2012.03.013.en_US
dc.identifier.citationPLoS ONE, 2012, e41141. doi: 10.1371/journal.pone.0041141.en_US
dc.identifier.citationPLoS ONE, 2013, e54280. Doi: 10.1371/journal.pone.0054280.en_US
dc.identifier.citationBioorganic Medicinal Chemistry Letters, 22, 2012, 1499-1503. doi: 10.1016/j.bmcl.2012.01.025.en_US
dc.identifier.urihttp://hdl.handle.net/1993/21708
dc.language.isoengen_US
dc.publisherAmerican Society for Microbiologyen_US
dc.publisherElsevieren_US
dc.publisherPublic Library of Scienceen_US
dc.publisherPublic Library of Scienceen_US
dc.publisherElsevieren_US
dc.rightsopen accessen_US
dc.subjectcationic amphiphilesen_US
dc.subjectlipopeptidesen_US
dc.subjectantibioticsen_US
dc.subjectantimicrobial peptidesen_US
dc.subjectaminoglycosidesen_US
dc.subjectimmunomodulatory peptidesen_US
dc.titleDesign and synthesis of cationic amphiphilesen_US
dc.typedoctoral thesisen_US
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