Gene-specific antibiotic development : evaluating effectiveness and investigating antibiotic-resistant Escherichia coli mutants of phosphorodiamidate morpholino oligomers Public

http://ir.library.oregonstate.edu/concern/honors_college_theses/x059c918w

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  • Phosphorodiamidate morpholino oligomers (PMOs) are novel antisense drugs in the early stages of development. These synthetic DNA mimics contain the same bases found in DNA and anneal to RNA in a complementary fashion. PMOs have been designed that target genes responsible for producing essential proteins in organisms such as Escherichia coli. After the PMOs get into the bacterial cell (with peptides attached to facilitate their entry), they block translation of the targeted gene by annealing to mRNA and kill the cell. In this way, PMOs can be used as antibiotics. Tests with varying concentrations of drugs were completed both in vitro and in vivo (with mice) showing that PMOs can be as effective as ampicillin in stopping a bacterial infection of E. coli. This thesis will cover some of these tests, as well as experiments in which PMO-resistant mutant strains were discovered and isolated. Further work with several peptide-PMO conjugates showed that resistance was not a result of a change in the PMO target sequence and appeared to be peptide-related. Finally, out of two experiments designed to pinpoint genes required for E. coli to be susceptible to peptide-PMOs, a transposon knock-out experiment was successful in generating a PMO-resistant mutant and singling out nmpC as a gene of interest. Though this gene is identified as a pseudogene on the BLAST website, this research suggests that nmpC could have a function. Future research with this gene as well as repeating this method to find other genes of interest may increase knowledge of how PMOs work and aid in the design of more effective PMOs.
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