Investigational peptide-based therapeutics: antibacterial agents, adjuvants and combinations thereof against Gram-negative bacteria

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dc.contributor.supervisor Schweizer, Frank (Chemistry) en_US
dc.contributor.author Domalaon, Ronald
dc.date.accessioned 2019-02-15T18:50:07Z
dc.date.available 2019-02-15T18:50:07Z
dc.date.issued 2019 en_US
dc.date.submitted 2019-02-05T22:18:24Z en
dc.identifier.uri http://hdl.handle.net/1993/33758
dc.description.abstract The alarming surge of multidrug-resistant bacterial pathogens able to repel and deactivate almost all clinically-used antibiotics drives our necessity to develop novel therapeutics, such as of peptide-based agents. Arguably, the problem of antimicrobial resistance is more serious in Gram-negative bacteria (GNB), relative to Gram-positive bacteria, as they typically carry multiple chromosomal-mediated resistance mechanisms and possess an intrinsic mechanism that restricts the entry of most antibiotics. This intrinsic resistance mechanism in GNB consists of the outer (OM) and inner membranes (IM), and overexpressed multidrug efflux systems. The OM and IM impose an orthogonal constraint on the type of molecules able to traverse intracellularly. The OM prevents the entry of large hydrophobic molecules while the IM prevents the diffusion of large hydrophilic molecules. Once the antibiotic enters the periplasm or the cytosol, it can then be efficiently expelled outside of the cell by a multitude of efflux pumps. Peptide-based agents, including naturally-occurring antimicrobial peptides and their mimics, usually target bacterial membranes. These membranotropic actions include perturbation of both the OM and IM (that can lead to lysis and intracellular component leakage), and sequestering of lipid components that may inactivate transmembrane proteins such as efflux pumps. The degree of membrane perturbation varies from each peptide, as some peptides result in overall membrane dissolution (lysis) while some induce only localized membrane disruption. My doctoral research work capitalized on this membranotropic mechanism to develop investigative peptide-based agents against GNB that either act as stand-alone antibiotics or as helper molecules, called adjuvants, in combination with other established antibiotics. In this context, peptide-based adjuvants enhance cellular entry of antibiotics by either inducing localized imperfections (pores) in membranes, that allow efficient diffusion of molecules, or sequestering lipid components surrounding transmembrane efflux pumps, that prevent the debilitating action of efflux. My work took inspiration from amphiphilic membrane-acting antimicrobial peptides to develop short synthetic investigative agents and adjuvants that in combination with clinically-used antibiotics can effectively eradicate GNB. Peptide-based agents and adjuvants in this thesis comprised of short proline-rich lipopeptides, dilipid ultrashort cationic lipopeptides and polymyxins derivatives. Specifically, polymyxin analogs in this thesis included dilipid polymyxins and polymyxin B3-tobramycin hybrids. en_US
dc.subject Antibacterial en_US
dc.subject Antimicrobial peptides en_US
dc.subject Drug combinations en_US
dc.subject Synergy en_US
dc.subject Gram-negative bacteria en_US
dc.subject Peptides en_US
dc.subject Medicinal chemistry en_US
dc.title Investigational peptide-based therapeutics: antibacterial agents, adjuvants and combinations thereof against Gram-negative bacteria en_US
dc.degree.discipline Chemistry en_US
dc.contributor.examiningcommittee O'Neil, Joe (Chemistry) en_US
dc.contributor.examiningcommittee Kumar, Ayush (Microbiology) en_US
dc.contributor.examiningcommittee Zhanel, George (Medical Microbiology & Infectious Diseases) en_US
dc.contributor.examiningcommittee Nitz, Mark (University of Toronto, Chemistry) en_US
dc.degree.level Doctor of Philosophy (Ph.D.) en_US
dc.description.note May 2019 en_US

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