Maltose Targeted Antibiotics

麦芽糖靶向抗生素

• 批准号: 8954854
• 负责人: NIREN MURTHY
• 金额: $ 20.46万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8954854
• 关键词: Acinetobacter; Antibiotics; Bacteria; Bacterial Infections; Biodistribution; Biological Availability; Bypass; C14 isotope; Cell Membrane Permeability; Clinical Trials; Data; Development; Drug Kinetics; Drug Targeting; Drug resistance; Escherichia coli; Food; Gram-Negative Bacteria; Gram-Positive Bacteria; High Pressure Liquid Chromatography; In Vitro; Infection; Klebsiella pneumonia bacterium; Label; Lactamase; Lead; Linezolid; Maltose; Mammalian Cell; Measures; Medicine; Modeling; Multi-Drug Resistance; Mus; Oligosaccharides; Oral; Oxazolidinones; Patients; Performance; Phase; Prodrugs; Pseudomonas aeruginosa; Public Health; Resistance; Ribosomes; Sepsis; Source; Technology; Testing; Therapeutic; Toxic effect; base; design; drug efficacy; efflux pump; improved; in vivo; innovation; intravenous injection; maltodextrin; mutant; novel therapeutics; pathogen; prevent; public health relevance; research study; resistance mechanism; targeted delivery

 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.

 描述（申请人提供）：开发针对耐药革兰氏阴性菌（GNB）的抗生素是医学的核心问题。开发针对GNB的抗生素一直具有挑战性，因为它们的膜渗透性低，这使得抗生素无法在GNB中达到治疗浓度。该提案的目的是开发一种新的策略，通过与硫代麦芽糖结合，增强抗生素向GNB的运输。硫代麦芽糖缀合的抗生素具有相对于游离抗生素显著增强的GNB的内化速率，因为它们通过麦芽糖糊精和其他寡糖转运蛋白进入细菌，麦芽糖糊精和其他寡糖转运蛋白是细菌的优选食物来源。此外，哺乳动物细胞不表达麦芽糖糊精和寡糖转运蛋白，因此硫代麦芽糖缀合的抗生素不应进入哺乳动物细胞，并且应具有比游离抗生素高得多的治疗窗。本提案中的实验将研究是否可以通过将药物雷德唑胺与硫代麦芽糖结合来改善其疗效。中央 该建议的假设是：与硫代麦芽糖缀合的雷得唑胺（称为TMR）在治疗耐药性GNB时将具有比游离雷得唑胺更宽的治疗窗，这是由于其增强的转运和较低的毒性。该假设基于我们的初步数据，该数据表明硫代麦芽糖结合雷得唑胺治疗耐药铜绿假单胞菌的有效性比游离雷得唑胺至少高2个数量级。我们将通过完成以下具体目标来检验本提案的中心假设：R21阶段具体目标1。通过与硫代麦芽糖特异性Aim 2结合，增加雷得唑胺转运至耐药GNB。 通过与硫代麦芽糖R33相结合增加雷得唑胺的疗效，特定目的1。通过与硫代麦芽糖特异性目标2结合，增加雷得唑胺对GNB的体内疗效。TMR的药代动力学及其口服生物利用度的优化该提案中的实验是创新的，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。该提案中的实验是重要的，因为它们将导致耐药GNB的新疗法的开发。