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Generation of SOS inhibitors as co-drugs to potentiate the activity of bactericidal antibiotics and to block the emergence of antibiotic resistance

dc.contributor.advisorGeyer, Ronen_US
dc.contributor.committeeMemberBlondeau, Josephen_US
dc.contributor.committeeMemberBull, Harolden_US
dc.contributor.committeeMemberSanche, Stephenen_US
dc.contributor.committeeMemberDeCoteau, Johnen_US
dc.creatorAlhhazmi, Areejen_US
dc.date.accessioned2013-09-16T19:52:05Z
dc.date.available2013-09-16T19:52:05Z
dc.date.created2012-04en_US
dc.date.issued2013-07-29en_US
dc.date.submittedApril 2012en_US
dc.description.abstractThe rapidly increasing emergence of antibiotic resistance amongst pathogenic bacteria is a major clinical and public health problem. The increase in resistant pathogens, accompanied with the small number of new antibiotics introduced in recent years, has limited the number of effective antimicrobials. The classical paradigm suggests that antibiotic resistance emerges by selection for pre-existing mutants in the bacterial population exposed to antibiotics. In contrast, recent data suggested that mutations evolve after cells encounter antibiotic therapy. This kind of mutation is known as adaptive mutation, which is activated by the SOS DNA repair and mutagenesis pathways. Accumulation of single-stranded DNA (ss-DNA) is the signal that induces the SOS response by promoting the formation of the RecA filament, which in turn activates the auto-cleavage activity of LexA and allows expression of SOS genes, including the SOS error-prone polymerases. In this project, phthalocyanine tetrasulfonic acid (PcTs)-based RecA inhibitors were characterized. PcTs molecules were found to potentiate the activity of bactericidal antibiotics and reduce the ability of bacteria to acquire antibiotic resistance mutations. This study highlights the ability of RecA inhibitors to potentiate the activity of antibiotics and provides a strategy for prolonging the life span of existing and newly developed antibiotics. We predicate that RecA inhibitors will be part of an antibiotic “cocktail” that enhances the activity of antibiotics and blocks resistance, which will ultimately prolong antibiotic lifespan.en_US
dc.identifier.urihttp://hdl.handle.net/10388/ETD-2012-04-434en_US
dc.language.isoengen_US
dc.subjectadaptive mutations, the SOS system, resistance, potentiation, antibioticsen_US
dc.titleGeneration of SOS inhibitors as co-drugs to potentiate the activity of bactericidal antibiotics and to block the emergence of antibiotic resistanceen_US
dc.type.genreThesisen_US
dc.type.materialtexten_US
thesis.degree.departmentMedicineen_US
thesis.degree.disciplineHealth Sciencesen_US
thesis.degree.grantorUniversity of Saskatchewanen_US
thesis.degree.levelMastersen_US
thesis.degree.nameMaster of Science (M.Sc.)en_US

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