Circumventing Tetracyline Resistance Mechanisms with Doxycyline-Conjugated Gold N

描述(申请人提供)：抗生素耐药感染的发生率正在迅速增加。这一趋势，再加上在过去20年中只引入了两类新的抗生素，许多制药公司已经停止了他们的抗生素研究努力，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的病原体，我们假设将耐药性妥协的药物结合到金纳米颗粒的表面将提供活性的抗生素结合物，从而克服典型的抗生素耐药机制。为了验证这一假设，我们将设计多西环素偶联的金纳米颗粒，以保持其结合30S RNA的能力，但不会激活四环素耐药性。我们还将展示这些颗粒有效地抑制四环素耐药细菌的生长。为了实现这一目标，本方案的两个具体目标是：1)设计和合成用于连接到金纳米颗粒上的硫代化四环素衍生物；2)评价抗菌性能和TetR结合识别能力。 与公共卫生相关：疾病控制中心表示，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了抗药性，并估计美国每年有200万人在医院(HAI)期间感染，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.