DNA gyrase and quinolone resistance in tuberculosis

结核病中的 DNA 旋转酶和喹诺酮耐药性

• 批准号: 7013574
• 负责人: KARL A DRLICA
• 金额: $ 64.44万
• 依托单位: PUBLIC HEALTH RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-30 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7013574
• 关键词: DNA; gyrase; quinolone; resistance; tuberculosis

DESCRIPTION (provided by applicant): The goals of this program are to understand how the quinolones act in mycobacteria and to discover ways to protect the compounds from the development of resistance. Previous work showed that structure modifications at the C-8 position of fluoroquinolones increase antibacterial activity, particularly with fluoroquinolone-resistant mutants. This feature, plus other variations in fluoroquinolone structure, will be examined to explore the hypothesis that lethal activity arises in part from the dissociation of gyrase subunits attached to cleaved DNA. Since gyrase subunit dissociation is assayed as lethal activity in the absence of protein synthesis, this work may reveal ways to improve action against nongrowing bacteria. To define how low fluoroquinolone concentrations affect the development of resistance, non-gyrase resistance mutants of Mycobacterium tuberculosis, obtained through selective growth at low drug concentration, will be examined for their ability to increase the frequency at which subsequent gyrase mutants are selectively enriched. This portion of the study is expected to influence fluoroquinolone dosing strategies. In patients, M. tuberculosis develops resistance so readily that anti-tuberculosis agents are administered as combination therapies; consequently, the lethal activity of new fluoroquinolones will be examined in combination with traditional agents to identify combinations of compounds that are unlikely to have intrinsic interfering activities. Traditional agents will also be combined with C-8-methoxy fluoroquinolones in a dynamic in vitro model to examine the effect of pharmacodynamic mismatch on the development of resistance. These two aspects of the program will help optimize the use of new fluoroquinolones. To provide a clinical context for the work, isolates from New York City will be examined for susceptibility to fluoroquinolones. Comparison of isolates obtained in the early 1990s with those obtained recently will indicate whether susceptibility is being lost. Principles emerging from these in vitro studies may be generally applicable to bacterial infections for which fluoroquinolone treatment is indicated; ideas concerning resistance may also extend to other compounds in which de novo antimicrobial resistance develops in a gradual, stepwise manner.

描述（由申请人提供）：该计划的目标是了解喹诺酮类在分枝杆菌中的作用，并发现保护化合物免受抵抗力发展的方法。先前的工作表明，在氟喹诺酮的C-8位置进行结构修饰会增加抗菌活性，尤其是在耐氟喹诺酮突变体的情况下。该特征以及氟喹诺酮结构的其他变化将检查以探讨以下假设：致命活性部分是由于连接到裂解DNA的回旋酶亚基的解离。由于在没有蛋白质合成的情况下将回旋酶亚基解离为致命活性，因此这项工作可能揭示了改善对非细菌作用的方法。为了确定低氟喹诺酮的浓度如何影响耐药性的发展，将检查通过在低药物浓度下选择性生长获得的结核分枝杆菌的非gyrase耐药性突变体，以确定其增加后续回旋酶突变体的频率的能力。该研究的这一部分有望影响氟喹诺酮剂量策略。在患者中，结核分枝杆菌的耐药性很容易，以至于抗结核药被作为联合疗法给药。因此，将研究新的氟喹诺酮类药物的致命活性与传统药物结合使用，以鉴定不太可能具有内在干扰活性的化合物组合。在动态的体外模型中，传统药物也将与C-8-甲氧基氟喹诺酮类药物结合使用，以检查药效不匹配对耐药性发展的影响。该程序的这两个方面将有助于优化新的氟喹诺酮类药物的使用。为了提供工作的临床环境，将检查纽约市的分离株，以使氟喹诺酮类药物的敏感性。 1990年代初获得的分离株与最近获得的分离株的比较将表明是否丢失了易感性。从这些体外研究中出现的原理通常适用于氟喹诺酮治疗的细菌感染。关于抗性的想法也可能扩展到其他化合物，在这些化合物中，从头抗菌素耐药性以逐步的逐步方式发展。