Ciprofloxacin resistance and compensatory Mutations.

描述(由申请人提供)： 人类病原微生物对抗生素耐药性的演变日益成为一个严重的公共卫生问题。已经提出了一些措施来打击抗生素耐药性的传播，并取得了不同程度的成功，包括控制抗生素的使用、疫苗的使用和改善医院卫生。然而，由于微生物种群抗性部分的进化变化，这种措施的最终成功是值得怀疑的。许多(但不是全部)抗生素耐药性突变是有害的，因此在缺乏抗生素的情况下可能会被选择对抗。然而，在长期接触抗生素的情况下，可以而且确实会发生并选择代偿性突变，这降低了与抗生素耐药性相关的成本。这种进化变化将导致耐药病原体的流行，并使一些抗生素失效。在这个国家炭疽病流行期间，这种情况将特别灾难性，环丙沙星将是首选的主要抗生素。该项目的主要重点将是表征和识别补偿性突变，这种突变可以降低枯草杆菌对环丙沙星的耐药性成本，枯草杆菌是炭疽杆菌的近亲。 这项研究还将扩大到包括大肠杆菌和另外两种抗生素，新诺明和头孢他啶。对代偿突变的生化和生理基础的了解可以使制定战略来减少或抵消它们在增加抗生素耐药突变流行率方面的作用。

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.