Small Molecules to Enhance Bacterial Susceptibility to Antiseptics

描述（由申请人提供）：与医院获得性感染（HAI）相关的费用中有三分之一归因于手术部位感染（SSI），SSI导致患者死亡率增加两倍。SSI最常由来自患者皮肤的植物群引起，这些植物群在切口部位进入身体并迅速复制以引起感染。虽然目前的 抗菌剂在杀死患者皮肤上的细菌方面有99.999%的有效性，剩余的生物体不成比例地具有耐药性，并且可能在患者中引起危及生命的感染。传统上，改进现有防腐剂的努力涉及引入新的活性杀生物剂，其仅提供对现有产品的增量改进。Agile Sciences联合创始人Christian Melander博士发现了一个独特的非杀微生物分子库，可以有效抑制细菌防御机制，使细菌对抗菌剂更敏感。这些化合物基于2-氨基咪唑（2-AI）亚基，靶向细菌双组分系统（TCS）的反应调节剂（RR），使细菌无法响应和适应外部损伤，如抗菌剂。雅居乐的2-AI分子经过综合优化，可增强杀菌产品的功效，包括葡萄糖酸氯己定（CHG），这是术前防腐剂中使用最广泛的活性成分。值得注意的是，2-AI化合物对革兰氏阳性和革兰氏阴性细菌都有效，初步毒性试验表明这些化合物对哺乳动物细胞和多细胞生物体无毒。这项工作的目标是评估敏捷的2-AI化合物的能力，以提高生物杀灭活性的 使用旨在模拟术前抗菌条件的体外试验，测定抗菌剂中的CHG活性成分。在具体目标#1中，2-AI分子与CHG结合的协同活性将在快速杀灭测定中进行评价，然后将活性化合物掺入抗菌制剂中并在皮肤样表面上进行评价。在特定目标#2中，将在体外进一步评估成功增强CHG对SSI中6种最常见细菌中至少5种的活性的化合物制剂的毒性和刺激潜力。该I期建议的成功度量是鉴定至少一种2-AI化合物，其提供CHG对至少5种测试细菌的杀灭活性的最小10倍增强，并且还显示可接受的毒性和皮肤刺激性特征。符合这一指标的化合物将在II期研究中进一步优化，目的是提供更有效的术前抗菌治疗，大大减少SSI的发生。 公共卫生相关性：在美国，每年有290，000名住院患者遭受手术部位感染，导致发病率和死亡率增加。敏捷科学公司正在开发一种改进的抗菌产品，其中包含一类新的强效小分子，以提高抗菌剂根除致病细菌的能力。

DESCRIPTION (provided by applicant): One-third of costs associated with hospital acquired infections (HAIs) are attributed to surgical site infections (SSIs), and SSIs result in a two-fold increase in patient mortality rates. SSIs are most often caused by flora from the patients skin that enter the body at the incision site and replicate rapidly to cause infection. Although current antiseptics are 99.999% effective at killing bacteria on patients skin, the remaining organisms are disproportionately drug-resistant, and may cause life-threatening infections in patients. Traditionally, efforts to improve upon existing antiseptics have involved introduction of new active biocidal agents that provide only incremental improvements over existing products. Agile Sciences co-founder, Dr. Christian Melander, has discovered a unique library of non-microbicidal molecules that effectively inhibit bacterial defense mechanisms so that bacteria are significantly more susceptible to antimicrobials. These compounds, based on a 2-aminoimidazole (2-AI) subunit, target the response regulator (RR) of bacteria's two component systems (TCSs) so that bacteria are unable to respond and adapt to external insults, such as antimicrobials. Agile's 2-AI molecules have been synthetically optimized to enhance the efficacy of microbicidal products, including chlorhexidine gluconate (CHG), which is the most widely-used active ingredient in pre-operative antiseptics. Notably, the 2-AI compounds are effective against both gram-positive and gram-negative bacteria, and preliminary toxicity tests indicate that these compounds are non-toxic to mammalian cells and multicellular organisms. The goal of this work is to assess the ability of Agile's 2-AI compounds to enhance biocidal activity of the CHG active ingredient in antiseptics using in vitro assays designed to mimic pre-operative antisepsis conditions. In Specific Aim #1, the synergistic activity of 2-AI molecules in conjunctio with CHG will be evaluated in a rapid kill assay, and then active compounds will be incorporated into an antiseptic formulation and evaluated on a skin-like surface. Compound formulations that successfully enhance the activity of CHG toward at least 5 of the 6 most prevalent bacteria in SSIs will be further assessed in vitro for toxicity and irritation potential in Specific Aim #2. Th metric of success of this Phase I proposal is to identify at least one 2-AI compound that provides a minimum of 10-fold enhancement in cidal activity of CHG toward at least 5 of the bacteria tested and also displays acceptable toxicity and skin irritation profiles. Compounds that meet this metric will be further optimized in a Phase II study with the goal of providing a more effective pre-operative antiseptic treatment that will substantially reduce the occurrence of SSIs. PUBLIC HEALTH RELEVANCE: Surgical site infections afflict 290,000 hospital patients in the US each year, resulting in increased morbidity and mortality. Agile Sciences is developing an improved antiseptic product that incorporates a new class of potent small molecules to enhance the ability of the antiseptic to eradicate pathogenic bacteria.