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Title: Antibiotic resistance and fitness costs in staphylococci
Author: Vickers, Anna
ISNI:       0000 0001 3546 9181
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2008
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Staphylococcus aureus is a highly successful pathogen that is responsible for causing a diverse spectrum ofhuman diseases (Casey et al., 2007). The challenge of treating staphylococcal infections is greatly complicated by the ability of organisms in this genus to evolve resistance to antimicrobial agents (Casey et al., 2007). The primary objective ofthe studies undertaken in this PhD project was to provide a greater understanding of the development of resistance to a number of clinically-relevant antimicrobial agents in S. aureus. Resistance to the fluoroquinolones, coumarins and trimethoprim was of particular interest, since these agents are potentially under-exploited with respect to their role in the management of staphylococcal infections (Vickers et al., 2007b). The development of resistance to the broad-spectrum antimicrobial tric10san was also a key interest, since this agent is becoming increasingly used, both for general decontamination in clinical and domestic environments, and for the specific elimination of methicillin-resistant S. aureus· (MRSA) carriage (Bayston et aI., 2007). Studies of resistance development focused primarily on mutation frequencies to resistance and fitness costs associate~ with resistance, since these parameters are key determinants for the emergence and survival of resistance genotypes in natural populations (Andersson, 2006). 111 ! i The studies described in Chapter 4 elucidated the mechanism of innate resistance to the coumarin antibiotic, novobiocin, in Staphylococcus saprophyticus. The molecular basis of this phenotype was of interest since uniform resistance to novobiocin is central to the identification of S. saprophyticus in the diagnostic laboratory. Chapter 5 examines triclosan resistance in S. aureus. Two novel triclosan resistance mutations were described in this work; these occurred at loci upstream of the structural gene jab!, which encodes the molecular target of triclosan.· It was hypothesised that the novel jab! mutations (A.72G and T-109G) confer resistance to triclosan by increasing transcription ofjab!. Chapter. 6 reports on the development of resistance to trimethoprim. Trimethoprim-resistant mutants occurred at relatively low frequencies, but resistance genotypes did not compromise the fitness of s. aureus in vitro, implying that trimethoprim-resistant strains may not face a selective disadvantage among natural bacter!al populations. Two novel trimethoprim resistance mutations were identified in this work (DHFR L41F and F99S). Molecular modeling techniques were used to explore the role of target protein (DHFR) mutations in resistance to trimethoprim and strongly suggested that DHFR mutations confer resistance to trimethoprim by reducing the affinity ofthe enzyme for trimethoprim. Chapter 7 provides insight into the fitness costs associated with a number of common staphylococcal resistance determinants. In general, expression of these determinants did not reduce the biological fitness of S. aureus in vitro.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available