Maltose Targeted Antibiotics

 描述(由申请人提供)：针对耐药革兰氏阴性细菌(GNB)的抗生素的开发是医学上的一个中心问题。开发针对GNB的抗生素一直是具有挑战性的，因为它们的膜通透性低，这阻碍了抗生素在GNB内达到治疗浓度。这项提议的目标是开发一种新的战略，通过与硫代麦芽糖的结合来加强抗生素向GNB的运输。硫代麦芽糖结合抗生素在GNB中的内化率比游离抗生素显著提高，因为它们通过麦芽糊精和其他寡糖转运蛋白进入细菌，而麦芽糊精和其他寡糖转运蛋白是细菌的首选食物来源。此外，哺乳动物细胞不表达麦芽糊精和低聚糖转运体，因此硫代麦芽糖结合的抗生素不应该进入哺乳动物细胞，并且应该比游离抗生素有更高的治疗窗口。这项提案中的实验将调查是否可以通过将药物雷德唑胺与硫代麦芽糖结合来提高其疗效。中环 这一提议的假设是：与硫代麦芽糖结合的雷德唑胺，称为TMR，由于其促进转运和较低的毒性，在治疗耐药GNB方面将比游离雷达唑胺有更宽的治疗窗口。这一假设是基于我们的初步数据，这表明硫代麦芽糖偶联雷达唑胺在治疗耐药铜绿假单胞菌方面比游离雷达唑胺至少有效2个数量级。我们将通过完成以下特定目标来检验这一建议的中心假设：R21期特异性目标1.通过与硫代麦芽糖特异性目标的连接增加雷达唑胺在耐药GNB中的转运2.通过与硫代麦芽糖R33期特异性目标的结合提高雷达唑胺的疗效1.通过与硫代麦芽糖特异性目标的结合提高雷达唑胺对GNB的体内疗效2.TMR的药代动力学及其口服生物利用度的优化本方案的实验具有创新性，因为他们开发了一种策略，可以将抗生素靶向GNB并增加其治疗窗口。这项提案中的实验意义重大，因为它们将导致抗药性GNB的新疗法的开发。

 DESCRIPTION (provided by applicant): The development of antibiotics against drug resistant gram negative bacteria (GNB) is a central problem in medicine. Developing antibiotics against GNB has been challenging because of their low membrane permeability, which prevents antibiotics from reaching therapeutic concentrations within GNB. The objective of this proposal is to develop a new strategy for enhancing the transport of antibiotics into GNB, via conjugation to thiomaltose. Thiomaltose conjugated antibiotics have internalization rates into GNB that are dramatically enhanced over free antibiotics because they enter bacteria via maltodextrin and other oligosaccharide transporters, which are the preferred food source for bacteria. In addition, mammalian cells do not express maltodextrin and oligosaccharide transporters, and therefore thiomaltose conjugated antibiotics should not enter mammalian cells and should have a much higher therapeutic window than free antibiotics. The experiments in this proposal will investigate if the efficacy of the drug radezolid can be improved by conjugating it to thiomaltose. The central hypothesis of this proposal is that: Radezolid conjugated to thiomaltose, termed TMR, will have a wider therapeutic window than free radezolid at treating drug resistant GNB, due to its enhanced transport and lower toxicity. This hypothesis is based on our preliminary data, which demonstrates that thiomaltose-conjugated radezolid is at least 2 orders of magnitude more effective at treating drug resistant P. aeruginosa than free radezolid. We will test the central hypothesis of this proposal by completing the following Specific Aims: R21 Phase Specific Aim 1. Increase the transport of radezolid into drug resistant GNB via conjugation to thiomaltose Specific Aim 2. Increase the efficacy of radezolid via conjugation to thiomaltose R33 Phase Specific Aim 1. Increase the in vivo efficacy of radezolid against GNB via conjugation to thiomaltose Specific Aim 2. Pharmacokinetics of TMR and optimization of its oral bioavailability The experiments in this proposal are innovative because they develop a strategy, which can target antibiotics to GNB and increase their therapeutic window. The experiments in this proposal are significant because they will lead to the development of new therapeutics for drug resistant GNB.