Circumventing Tetracyline Resistance Mechanisms with Doxycyline-Conjugated Gold N

描述（由申请人提供）：抗生素耐药感染的发生率正在迅速增加。这种趋势，加上在过去二十年中仅引入了两类新的抗生素以及许多制药公司已经停止了抗生素研究工作的事实，导致了许多细菌感染极难/不可能治疗的情况。为了对抗这些多重耐药病原体，我们已经假定，将耐药性受损的药物缀合到金纳米颗粒的表面将递送克服典型抗生素耐药性机制的活性抗生素缀合物。为了验证这一假设，我们将设计多西环素缀合的金纳米颗粒，保持其结合30 S RNA的能力，但不激活四环素抗性。我们还将证明这些颗粒有效地抑制四环素耐药菌的生长。为了实现这一目标，本提案的两个具体目标是：1）设计和合成用于与金纳米颗粒缀合的硫醇化四环素衍生物和2）评价抗菌特性和TetR结合辨别。 公共卫生相关性：疾病控制中心已经指出，世界上几乎所有重要的细菌物种都对抗生素治疗方案产生耐药性，并且估计每年美国将有200万人在医院（HAI）中感染，导致10万人死亡。据估计，这些HAI每年造成300亿美元的直接成本。

DESCRIPTION (provided by applicant): The incidence of antibiotic resistant infections is rapidly increasing. This trend, coupled with the fact that only two new classes of antibiotics have been introduced in the last two decades and many pharmaceutical companies have discontinued their antibiotic research efforts, have led to a situation in which many bacterial infections are extremely difficult/impossible to treat. To combat these multi-drug resistant pathogens, we have posited that conjugating resistance-compromised drugs to the surface of gold nanoparticles will deliver active antibiotic conjugates that overcome typical antibiotic resistance mechanisms. To validate this hypothesis, we will design doxycycline-conjugated gold nanoparticles that maintain their ability to bind 30S RNA but do not activate tetracycline resistance. We will also demonstrate that these particles potently inhibit growth of tetracycline resistant bacteria. To achieve this goal, the two specific aims of this proposal are: 1) To design and synthesize a thiolated tetracycline derivative for conjugation to a gold nanoparticle and 2) Evaluation of antibacterial properties and TetR binding discrimination. PUBLIC HEALTH RELEVANCE: The Center for Disease Control has indicated that virtually all significant bacterial species in the world are becoming resistant to antibiotic treatment regimens, and estimates that each year 2 million people in the US will acquire an infection while in a hospital (HAI), resulting in 100,000 deaths. These HAIs are estimated to result in $30 billion of direct costs annually.