Small Molecules to Enhance Bacterial Susceptibility to Antiseptics

小分子增强细菌对抗菌剂的敏感性

• 批准号: 8395175
• 负责人: Angela Marie Pollard
• 金额: $ 25.72万
• 依托单位: AGILE SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-10 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8395175
• 关键词: Adjuvant; Antisepsis; Bacteria; Bacterial Counts; Biocide; Biological Assay; Bypass; Chemistry; Chlorhexidine; Defense Mechanisms; Drug Formulations; Drug resistance; Ethanol; Goals; Gram-Negative Bacteria; Hospitals; In Vitro; Incidence; Infection; Lead; Libraries; Life; Local Anti-Infective Agents; Mammalian Cell; Metric; Morbidity - disease rate; Multi-Drug Resistance; Nosocomial Infections; OmpR protein; Operative Surgical Procedures; Organism; Patients; Phase; Povidone-Iodine; Predisposition; Prevalence; Property; Science; Site; Skin; Small Business Innovation Research Grant; Stimulus; Surface; Surgical incisions; System; Technology; Testing; Toxic effect; Toxicity Tests; Work; antimicrobial; bacterial resistance; base; cost; design; gluconate; implantable device; improved; in vitro Assay; innovation; irritation; killings; meetings; methicillin resistant Staphylococcus aureus; microbicide; mortality; pathogenic bacteria; phase 2 study; professor; resistance mechanism; response; skin irritation; small molecule; success

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.

描述（由申请人提供）：与医院获得的感染相关的成本的三分之一归因于手术部位感染（SSIS），SSIS导致患者死亡率增加了两倍。 SSI通常是由患者皮肤的菌群引起的，这些菌群进入切口部位，并迅速复制以引起感染。虽然是最新的 抗菌素有效地杀死患者皮肤的细菌，其余生物的抗药性为99.999％，其耐药性不成比例，并且可能导致患者的生命危险感染。传统上，改善现有防腐剂的努力涉及引入新的活跃杀生物剂，这些杀菌剂仅提供对现有产品的增量改进。敏捷科学联合创始人克里斯蒂安·梅兰德（Christian Melander）博士发现了一个独特的非微生物分子库，这些库有效地抑制了细菌防御机制，从而使细菌更容易受到抗菌剂的影响。这些化合物基于2-氨基咪唑（2-AI）亚基，靶向细菌的两个成分系统（TCSS）的反应调节剂（RR），因此细菌无法反应并适应外部侮辱，例如抗菌病。敏捷的2-AI分子已被合成优化，以增强杀菌产物的疗效，包括氯己定（CHG），这是术前抗菌药物中最广泛使用的活性成分。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均有效，初步毒性测试表明，这些化合物对哺乳动物细胞和多细胞生物无毒。这项工作的目的是评估敏捷2-AI化合物增强杀菌活性的能力 CHG使用旨在模仿术前反蛋白质条件的体外测定的抗菌素活性成分。在特定的目标＃1中，将在快速杀死测定中评估2-AI分子在结膜中的协同活性，然后将活性化合物掺入抗菌式配方中，并在皮肤样表面上进行评估。成功增强CHG对SSI中6个最普遍的细菌中至少5种的活性的复合制剂将在体外进一步评估特定目标＃2的毒性和刺激潜力。该阶段I提案成功的指标是鉴定至少一种2-AI化合物，该化合物至少可以在CHG的CIDAL活动中提高至少5种经过测试的细菌，并显示可接受的毒性和皮肤刺激性。符合该指标的化合物将在II期研究中进一步优化，其目的是提供更有效的术前抗菌治疗，从而大大减少SSIS的发生。 公共卫生相关性：每年在美国290,000名医院患者的手术部位感染，导致发病率和死亡率增加。敏捷科学正在开发一种改进的杀菌产物，该产物融合了一类新的有效小分子，以增强杀菌剂消除致病细菌的能力。