Maltodextrin based antibiotics

描述(申请人提供)：耐药革兰氏阴性细菌是世界上死亡和发病的主要原因，非常需要新的治疗策略。这项提议的目的是开发一种新的靶向环丙沙星进入耐药革兰氏阴性细菌的策略，由麦芽六糖与抗生素结合组成。麦芽六糖结合的抗生素旨在通过麦芽糊精(MD)转运蛋白由细菌选择性地输入，但由于哺乳动物细胞缺乏MD转运蛋白，因此应该最小限度地内化到哺乳动物细胞。麦芽六糖结合抗生素在内化后被设计为被切割，并在细菌细胞质内释放出游离的抗生素。这一提议的中心假设是麦芽六糖与环丙沙星的偶联物MDC-1和MDC-2将被转运到耐药铜绿假单胞菌中，比游离的环丙沙星高10倍，并将相对于游离的环丙沙星具有更强的抗生素效力。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将有比游离环丙沙星更宽的治疗窗口。该提案的总体目标将通过以下具体目标检验我们的中心假设来实现：R21，阶段特定目标1.MDC-1和MDC-2的合成和细胞内转运。具体目的2.MDC-1和MDC-2对耐药铜绿假单胞菌的抗菌活性。R21期实验的完成将证明，通过将环丙沙星与麦芽糊精结合，可以提高环丙沙星的疗效。这些研究将为随后的R33阶段奠定基础，R33阶段的重点是研究MDC-1和MDC-2在对抗细菌感染方面的体内治疗效果和一般性。R33期，特异靶1。测定MDC-1和MDC-2的体内疗效。具体目的2.测定MDC-1和MDC-2对革兰氏阴性杆菌的抗菌活性。这项计划中的实验具有创新性，因为它们将首次开发一种将药物靶向细菌的小分子策略，并首次尝试利用麦芽糊精的运输途径进行药物输送。拟议的项目意义重大，因为它有可能产生一个通用平台，用于加强将结构多样化的抗生素输送到多重耐药细菌中。因此，这一新方法有可能通过减少抗菌素耐药生物的出现并刺激新型抗生素的开发，从而显著影响医学、公共卫生和国家安全。

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.