A major factor that affects the emergence and survival of resistant strains is the biological cost of resistance. Thus, to reduce the rate of spread of resistant bacteria we need to identify antibiotic targets and antibiotics for which the resistance mecha nisms have the most negative effects on bacterial fitness. Thus, the overall aims of this proposal are to experimentally examine and define in several medically important species how fitness, virulence and transmission are affected by different types of an tibiotic resistance. Such knowledge is a prerequisite for: (i) predicting the rate and stability of resistance development, (ii) developing novel diagnostic test systems for resistant bacterial clones with a high risk of resistance development, (iii) forec asting the value of intervention strategies and (iv) rational design of antibiotics and choice of antibiotic targets where the potential for resistance development is minimized. We intend to address in eight different work packages the following questions. 1. How does different resistance mechanims affect bacterial fitness and physiology (WP1-3)? 2. How can the fitness costs of antibiotic resistance be genetically compensated (WP3)? 3. How does different resistance mechanims affect transmission rates in ani mal models (WP4), volunteers (WPS) and clinical settings (WP6)? 4. Can thew prevalence of antibiotic resistance be reduced in human populations by lowering the volume of use of antibiotics (WP7)? 5. Can antibiotics and targets be rationally chosen such tha t the rate of resistance development is minimized (WP8)?
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