Maltodextrin based antibiotics

描述（由申请人提供）：耐药革兰氏阴性菌是世界上造成死亡和发病的主要原因，迫切需要新的治疗策略。本研究的目的是开发一种新的策略，将环丙沙星靶向耐药革兰氏阴性菌，该策略由麦芽糖己糖与抗生素偶联组成。麦芽糖己糖偶联抗生素被设计为通过麦芽糖糊精（MD）转运体选择性地由细菌输入，但由于缺乏MD转运体，哺乳动物细胞应尽量减少内化。在内化后，麦芽糖己糖偶联抗生素被设计成在细菌细胞质内裂解并释放游离抗生素。该提案的中心假设是麦芽糖己糖与环丙沙星的结合物，称为MDC-1和MDC-2，将以比游离环丙沙星大10倍的速度被转运到耐药铜绿假单胞菌中，并且相对于游离环丙沙星具有更高的抗生素效力。此外，我们假设在肺部感染模型中，MDC-1和MDC-2在治疗耐药铜绿假单胞菌方面比游离环丙沙星有更宽的治疗窗口。本提案的总体目标将通过以下具体目标来测试我们的中心假设来实现：R21，阶段具体目标1。MDC-1和MDC-2的合成和细胞内转运。具体目标2。MDC-1和MDC-2对耐药铜绿假单胞菌的抑菌活性。R21期实验的完成将证明环丙沙星与麦芽糊精偶联可以提高其治疗效果。这些研究将作为后续R33期的基础，R33期的重点是研究MDC-1和MDC-2在对抗细菌感染方面的体内治疗效果和普遍性。R33阶段，特异性目标1。测定MDC-1和MDC-2的体内疗效。具体目标2。测定MDC-1和MDC-2对革兰氏阴性菌的作用。本提案中的实验具有创新性，因为它们将首次开发出针对细菌的小分子药物策略，并代表了利用麦芽糊精转运途径进行药物递送的首次尝试。拟议的项目意义重大，因为它有可能产生一个通用平台，以加强结构多样的抗生素向多药耐药细菌的输送。因此，这种新方法有可能通过减少抗菌素耐药生物的出现和刺激新型抗生素的开发，对医学、公共卫生和国家安全产生重大影响。

DESCRIPTION (provided by applicant): Drug resistant Gram-negative bacteria are a major cause of mortality and morbidity in the world and new strategies for treating them are greatly needed. The objective of this proposal is to develop a new strategy for targeting ciprofloxacin into drug-resistant Gram-negative bacteria, composed of conjugating maltohexaose to antibiotics. Maltohexaose-conjugated antibiotics are designed to be selectively imported by bacteria via the maltodextrin (MD) transporter, but should be minimally internalized by mammalian cells due to their lack of MD transporters. After internalization, maltohexaose conjugated antibiotics are designed to be cleaved and release the free antibiotic within the bacterial cytoplasm. The central hypothesis of this proposal is that conjugates of maltohexaose with ciprofloxacin, termed MDC-1 and MDC-2, will be transported into drug-resistant P. aeruginosa by a factor of 10 greater than free ciprofloxacin, and will have increased antibiotic potency relative to that of free ciprofloxacin. In addition, we hypothesize that MDC-1 and MDC-2 will have a wider therapeutic window than free ciprofloxacin at treating drug resistant P. aeruginosa in a lung infection model. The overall objective of this proposal will be accomplished by testing our central hypothesis through the following Specific Aims: R21, Phase Specific Aim 1. Synthesis and intracellular transport of MDC-1 and MDC-2. Specific Aim 2. Antibacterial activity of MDC-1 and MDC-2 against drug resistant P. aeruginosa. The completion of the R21 phase experiments will demonstrate that the therapeutic efficacy of ciprofloxacin can be improved by conjugating it to maltodextrins. These studies will serve as the foundation for the subsequent R33 phase, which focuses on investigating the in vivo therapeutic efficacy and generality of MDC-1 and MDC-2 in fighting bacterial infections. R33 Phase, Specific Aim 1. Determine the in vivo efficacy of MDC-1 and MDC-2. Specific Aim 2. Determine the efficacy of MDC-1 and MDC-2 against Gram-negative bacteria. The experiments in this proposal are innovative because they will for the first time develop a small molecule strategy for targeting drugs to bacteria, and represent the first attempt to exploit the maltodextrin transport pathway for drug delivery. The proposed project is significant because it has the potential to generate a universal platform for enhancing the delivery of structurally diverse antibiotics into multidrug resistant bacteria. This new approach therefore has the potential to significantly impact medicine, public health and national security by reducing the emergence of antimicrobial-resistant organisms and stimulating the development of novel antibiotics. PUBLIC HEALTH RELEVANCE: The experiments in this proposal will lead to the development of a new strategy for targeting antibiotics to drug resistant bacteria, based on conjugating antibiotics to maltodextrins, termed MDCs. The MDCs can selectively deliver high concentrations of antibiotics into bacteria via transport through the bacteria specific maltodextri pathway. This new strategy therefore has the potential to enhance the efficacy of existing antimicrobial therapeutics and also revitalize "ineffective" new antimicrobial agents that suffered from systemic toxicity and poor membrane permeability.