Drug resistance in tuberculosis: genetic and dynamics

描述(由申请人提供) 结核病仍然是世界范围内的一个主要公共卫生问题。管理层 最近，随着结核病发病率的上升，结核病的防治变得越来越困难 耐药疾病的发病率。致病微生物--分枝杆菌 结核病，对许多常见的抗生素具有天生的抗药性，并会积累 允许对多种抗生素产生抗药性的突变。现在的抵抗 有必要使用效力较弱、毒性较大的二线药物 治疗许多感染的病人。而耐药机制 已经确定了几个第一线特工，对第二个人知之甚少 一线毒品。 我们建议研究两者抗性的分子机制。 抗分枝杆菌抗生素和非常用治疗药物 肺结核。我们将利用产生和分析转座子的方法 我们最近开发的突变体。这些方法已经 确定了导致耐药性的以前未知的突变。我们 也将研究结核分枝杆菌在感染期间的种群动态 一只老鼠模型。我们的数学模型表明，药物效力和 抗性的生理“成本”(对生长速度的影响)在 抗药性的发展比突变率更高，观察到 影响抗生素治疗策略的设计。我们将使用“已标记” 菌株要跟随个别菌株的命运，无论是药物敏感还是药物敏感 在感染期间具有抵抗力。这将使我们能够比较 菌株的适合度和在存在的情况下确定耐药性的成本 以及缺乏抗生素治疗。这些研究的结果将是 有助于开发新的抗生素治疗方法和策略

DESCRIPTION (provided by applicant) Tuberculosis remains a major public health problem worldwide. The management of tuberculosis has recently become increasingly difficult with the rising incidence of drug resistant disease. The causative organism, Mycobacterium tuberculosis, is innately resistant to many common antibiotics and accumulates mutations that allow resistance to multiple antibiotics. Resistance now necessitates the use of less potent and more toxic second line drugs for treatment of many infected patients. While the mechanisms of drug resistance to several first line agents has been determined, little is known about second line drugs. We propose to investigate the molecular mechanisms of resistance to both antimycobacterial antibiotics and agents not ordinarily used to treat tuberculosis. We will utilize methods for generating and analyzing transposon mutants that we have recently developed. These methods have already identified previously unknown mutations responsible for drug resistance. We will also study the population dynamics of M. tuberculosis during infection in a mouse model. Our mathematical model suggests that drug potency and the physiologic "cost" (effect on growth rate) of resistance are more important in the development of resistance than mutation rate, an observation that would affect the design of antibiotic treatment strategies. We will use "tagged" strains to follow the fate of individual strains, both drug sensitive and drug resistant, during infection. This will allow us to compare the relative fitness of strains and determine the cost of drug resistance in the presence and absence of antibiotic treatment. The results of these studies will be useful for developing new antibiotic treatments and strategies