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      • HARVEST
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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

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      ALHHAZMI-THESIS.pdf (2.317Mb)
      Date
      2013-07-29
      Author
      Alhhazmi, Areej
      Type
      Thesis
      Degree Level
      Masters
      Metadata
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      Abstract
      The 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.
      Degree
      Master of Science (M.Sc.)
      Department
      Medicine
      Program
      Health Sciences
      Supervisor
      Geyer, Ron
      Committee
      Blondeau, Joseph; Bull, Harold; Sanche, Stephen; DeCoteau, John
      Copyright Date
      April 2012
      URI
      http://hdl.handle.net/10388/ETD-2012-04-434
      Subject
      adaptive mutations, the SOS system, resistance, potentiation, antibiotics
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