Maltodextrin based antibiotics

描述（由申请人提供）：耐药革兰氏阴性菌是世界上死亡率和发病率的主要原因，非常需要治疗它们的新策略。本提案的目的是开发一种将环丙沙星靶向至耐药革兰氏阴性菌的新策略，该策略由麦芽六糖缀合至抗生素组成。麦芽六糖缀合的抗生素被设计为通过麦芽糊精（MD）转运蛋白被细菌选择性地输入，但由于它们缺乏MD转运蛋白，因此应该被哺乳动物细胞最小限度地内化。在内化后，麦芽六糖缀合的抗生素被设计为在细菌细胞质内被切割并释放游离抗生素。该提议的中心假设是麦芽六糖与环丙沙星的缀合物（称为MDC-1和MDC-2）将以比游离环丙沙星大10倍的因子被转运到耐药性铜绿假单胞菌中，并且相对于游离环丙沙星具有增加的抗生素效力。此外，我们假设MDC-1和MDC-2在治疗肺部感染模型中的耐药性铜绿假单胞菌时将具有比游离环丙沙星更宽的治疗窗。本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对耐药性铜绿假单胞菌的抗菌活性。R21阶段实验的完成将证明环丙沙星的治疗功效可以通过将其与麦芽糖糊精缀合来改善。这些研究将作为后续R33阶段的基础，该阶段的重点是研究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阶段，具体目标1。确定MDC-1和MDC-2的体内功效。具体目标2。确定MDC-1和MDC-2对革兰氏阴性菌的效力。该提案中的实验具有创新性，因为它们将首次开发出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转运途径进行药物递送。拟议的项目意义重大，因为它有可能产生一个通用平台，用于增强结构多样的抗生素向多重耐药细菌的递送。因此，这种新方法有可能通过减少耐药性微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.