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 结核病的治疗最近变得越来越困难， 耐药疾病的发生率。 病原体分枝杆菌 结核病对许多常见抗生素具有先天耐药性， 突变导致对多种抗生素产生耐药性。 现在抵抗 需要使用效力较低和毒性更大的二线药物， 治疗许多感染者。 虽然耐药机制 几个一线代理商已经确定，很少有人知道第二 毒品 我们建议研究耐药的分子机制， 抗分枝杆菌抗生素和通常不用于治疗 结核 我们将利用产生和分析转座子的方法 我们最近开发的变种人 这些方法已经 发现了以前未知的导致耐药性的突变。 我们 并将研究M.结核病感染期间， 一个老鼠模型。我们的数学模型表明，药物效力和 抗性的生理“代价”（对生长速度的影响）在 耐药性的发展比突变率，观察， 影响抗生素治疗策略的设计。 我们将使用“标记” 菌株跟踪单个菌株的命运，包括药物敏感菌株和药物敏感菌株。 在感染期间具有抵抗力。 这将使我们能够比较 菌株的适应性，并确定存在耐药性的成本 和缺乏抗生素治疗。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