Investigating the resistance that arises in Escherichia coli towards the furazolidone – vancomycin antibiotic combination : Master of Science (Biological Sciences) at Massey University, Manawatū, New Zealand

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Massey University
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Antibiotic resistance is a major threat to our current healthcare system. As bacterial resistance mechanisms continue to develop and spread, more and more antibiotics are becoming less and less effective, making an increasing number of bacterial infections difficult or even impossible to treat. Worryingly, bacterial antibiotic resistance is outpacing the rate of development of new antibiotics, making a return to the pre antibiotic era a very real possibility. In particular, additional strategies are required to tackle gram-negative pathogens, the most pressing threat. One additional strategy is to utilise existing antibiotics in new combinations. This thesis investigates the resistance development towards the furazolidone – vancomycin antibiotic combination in Escherichia coli. The synergistic FZ – VAN combination has been previously shown to be a promising potential combination against gram-negative pathogens, repurposing vancomycin, used against gram-positive pathogens, against gram-negative bacteria. By investigating the resistance development towards this combination, insight into the ease of resistance development and types of resistance development can be had, leading to increased understanding of the resistance mechanisms and potential use of this combination. Resistance towards the FZ – VAN combination was selected for, and the isolated strains underwent comparative genome analysis, revealing the genomic changes behind their observed phenotypic resistance. Mutations affecting seven main genes were identified as potential causes of resistance, ribE, ribB, ftsH, rpoC, opgG, wecC, and nlpI. In addition, the mechanism of resistance to FZ by the ribB and ribE riboflavin biosynthesis mutants was investigated. These mutations were found to result in a lower nitroreductase activity, predominantly affecting the key nitrofuran-activating nitroreductases NfsA and NfsB.