Identification of potentiators of antimicrobial activity against multidrug-resistant Burkholderia cepacia complex infections in cystic fibrosis

囊性纤维化中多重耐药洋葱伯克霍尔德杆菌复合感染抗菌活性增强剂的鉴定

• 批准号: 10358653
• 负责人: Thea Brennan-Krohn
• 金额: $ 21.88万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10358653
• 关键词: Address; Affect; Albumins; American; Amino Acids; Anaerobic Bacteria; Animal Model; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antidepressive Agents; Antimicrobial susceptibility; Avidity; Bacteria; Biological Assay; Burkholderia cepacia complex; Ceftazidime; Characteristics; Chloride Channels; Clinical; Collection; Cystic Fibrosis; DNA; Development; Disease; Dose; Drug resistance; Environment; Evaluation; Exposure to; FDA approved; Fright; Future; Gastrointestinal tract structure; Genetic Diseases; Goals; Gram-Negative Bacteria; Growth; Hospitalization; Human; In Vitro; Individual; Infection; Inhalation; Investigation; Iron; Levaquin; Life; Longevity; Lung; Lung infections; Meropenem; Microbial Biofilms; Minocycline; Mucins; Mucous body substance; Multi-Drug Resistance; Nebulizer; Organism; Oxygen; Patients; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Property; Pulmonary Cystic Fibrosis; Quality of life; Regimen; Research; Research Project Grants; Resistance; Respiratory System; Selective Serotonin Reuptake Inhibitor; Sertraline; Speed; Sputum; Techniques; Testing; Therapeutic; Time; Tobramycin; Trimethoprim-Sulfamethoxazole; United States; Viscosity; Work; alternative treatment; antimicrobial; bench to bedside; clinical practice; cystic fibrosis infection; cystic fibrosis patients; design; effective therapy; emerging antibiotic resistance; high throughput screening; improved; in vitro Model; in vitro activity; lung colonization; mortality; multi-drug resistant pathogen; novel; novel therapeutics; pathogen; pressure; prevent; resistance mechanism; resistant strain; response; scaffold; small molecule; synergism; systemic toxicity; treatment strategy

Project Summary/Abstract Pulmonary exacerbations are one of the most common manifestations of cystic fibrosis (CF), a life-limiting, multisystem disease that affects 30,000 Americans. These exacerbations are often caused by highly drug- resistant Gram-negative bacteria that colonize the lungs of people with CF. Among such organisms, the most feared is the Burkholderia cepacia complex (Bcc). Bcc have extensive intrinsic antibiotic resistance and readily acquire further resistance mechanisms under selective pressure during antibiotic treatment; pan-resistant strains can emerge following repeated antibiotic courses. Bcc infection is associated with frequent hospitalizations and increased mortality in people with CF, but there are no new antibiotics with activity against BCC in the development pipeline, and alternative treatment strategies are urgently needed. The goal of the proposed research is to identify known bioactive compounds that have activity against Bcc either alone or in combination with antibiotics. This work will be carried out through two aims. In Aim 1, we will test 14,000 known bioactive small molecules, including all FDA-approved drugs, both alone and in combination with six antibiotics commonly used to treat Bcc (meropenem, ceftazidime, minocycline, levofloxacin, trimethoprim-sulfamethoxazole, and tobramycin, each at an individually ineffective concentration), to identify compounds and compound/antibacterial combinations that inhibit growth of a representative Bcc isolate. In Aim 2, we will further characterize the activity of promising compounds identified in the screen using several complementary in vitro models. First, we will perform spectrum-of-activity and dose-response testing of compounds and combinations against a collection of 30 Bcc isolates using inkjet printer-assisted checkerboard array synergy studies as well as time-kill synergy studies. We will also evaluate the capacity of compounds to prevent the emergence of antibiotic resistance during treatment. Then, in order to better approximate the environment in which bacteria live in the lungs of people with CF, which is characterized by increased viscosity, high concentrations of mucin, albumin, amino acids, and free DNA, and lower oxygen tension relative to standard in vitro antimicrobial susceptibility testing conditions, we will test compounds and combinations using an artificial sputum medium in a microaerophilic environment. With this approach, we will assess whether activity is maintained under conditions more closely resembling those in which they would be used in clinical practice. When the project is completed, we expect to have identified a collection of molecules with previously unrecognized activity against Bcc and to have determined which of these are most likely to be clinically effective in people with CF. Identification of well-characterized compounds that have potential therapeutic activity against Bcc will facilitate future evaluation in animal models and human trials in order to develop desperately needed new therapeutic options for Bcc.

项目概要/摘要 肺部病情加重是囊性纤维化 (CF) 最常见的表现之一，囊性纤维化是一种限制生命的疾病 影响 30,000 美国人的多系统疾病。这些恶化通常是由高度药物引起的 定植于 CF 患者肺部的耐药革兰氏阴性细菌。在此类生物中，最 令人担心的是洋葱伯克霍尔德菌复合体（Bcc）。 Bcc 具有广泛的内在抗生素耐药性，并且很容易 在抗生素治疗过程中，在选择压力下获得进一步的耐药机制；泛抗性菌株 重复使用抗生素疗程后可能会出现。 Bcc 感染与频繁住院有关 CF 患者的死亡率增加，但目前尚无针对 BCC 活性的新抗生素 迫切需要开发管道和替代治疗策略。拟议的目标 研究旨在识别已知的生物活性化合物，这些化合物单独或组合具有抗 Bcc 活性 与抗生素。这项工作将通过两个目标进行。在目标 1 中，我们将测试 14,000 种已知的生物活性物质 小分子，包括所有 FDA 批准的药物，通常单独使用或与六种抗生素联合使用 用于治疗 BCC（美罗培南、头孢他啶、米诺环素、左氧氟沙星、甲氧苄啶-磺胺甲恶唑和 妥布霉素，每种都处于单独无效的浓度），以鉴定化合物和化合物/抗菌剂 抑制代表性 Bcc 分离株生长的组合。在目标 2 中，我们将进一步描述该活动的特征 使用几种互补的体外模型筛选中鉴定出的有前途的化合物。首先，我们将 针对一组化合物和组合进行活性谱和剂量反应测试 使用喷墨打印机辅助棋盘阵列协同研究以及节省时间的协同作用进行 30 Bcc 分离 研究。我们还将评估化合物在过程中防止抗生素耐药性出现的能力。 治疗。然后，为了更好地模拟细菌在患者肺部生存的环境 CF，其特点是粘度增加，粘蛋白、白蛋白、氨基酸和游离态浓度高 DNA，以及相对于标准体外抗菌药敏测试条件较低的氧张力，我们将 在微需氧环境中使用人工痰介质测试化合物和组合。有了这个 方法，我们将评估是否在更接近于那些条件下维持活动 它们将用于临床实践。当项目完成时，我们期望已经确定了一个集合 具有先前未被识别的针对 Bcc 活性的分子，并确定其中哪些是最重要的 可能对 CF 患者具有临床效果。鉴定具有良好特征的化合物 针对 BCC 的潜在治疗活性将有助于未来在动物模型和人体试验中进行评估 为了开发 BCC 急需的新治疗方案。