Ciprofloxacin resistance and compensatory mutations

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DESCRIPTION (provided by applicant): The evolution of antibiotic resistance in human pathogenic microorganisms is increasingly becoming a serious public health problem. A number of measures have been proposed to combat the spread of antibiotic resistance with varying success, including controls of the use of antibiotics, the use of vaccines and improvement of hospital hygiene. However, the ultimate success of such measures is questionable, due to evolutionary changes in the resistant sector of the microorganism populations. Many (but not all) mutations to antibiotic resistance are deleterious, and therefore may be selected against in the absence of the antibiotic. However, under prolonged exposure to antibiotics, compensatory mutations can and do occur and be selected, which reduce the cost associated with antibiotic resistance. Such evolutionary changes will contribute to the prevalence to antibiotic resistant pathogens, and render some antibiotics ineffective. Such a scenario will be particularly disastrous during an anthrax epidemic in this country, for which ciprofloxacin will be the primary antibiotic of choice. The principal focus of this project will be to characterize and identify compensatory mutations, which reduce the cost of ciprofloxacin resistance in B. subtilis, a close relative of B. anthracis. The study will also be extended to include E. coli and two other antibiotics, novobiocin and ceftazidime. Knowledge of the biochemical and physiological basis of compensatory mutations may allow the design of strategies to reduce or counteract their role in increasing the prevalence of antibiotic resistant mutations.