Novel Antibiofilm Treatments for Pseudomonas aeruginosa Infection

治疗铜绿假单胞菌感染的新型抗菌膜疗法

• 批准号: 10648172
• 负责人: JONATHAN W HARDY
• 金额: $ 7.5万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10648172
• 关键词: Animal Model; Animals; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Antibiotic Resistance; Berberine; Biological; Biological Assay; Cessation of life; Chronic; Ciprofloxacin; Combined Antibiotics; Complex; Creosote; Development; Dose; Exclusion; FDA approved; Goals; Goldenseal; Hour; Hydrastis; In Vitro; Individual; Infection; Intervention; Larrea; Lung infections; Measures; Mediating; Microbial Biofilms; Modeling; Mus; Natural Products; Persons; Pharmaceutical Preparations; Phytochemical; Plant Extracts; Plants; Process; Property; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Regimen; Reporting; Research; Resistance; Source; Speed; Structure; System; Testing; Therapeutic; Time; Tobramycin; Treatment Protocols; Triclosan; Water; Wound Infection; Wound models; antimicrobial; bacterial metabolism; bacterial resistance; bioluminescence imaging; combat; design; efficacy testing; experimental study; high throughput screening; in vivo; in vivo bioluminescence imaging; in vivo evaluation; innovation; mouse model; multidrug-resistant Pseudomonas aeruginosa; natural antimicrobial; non-invasive imaging; novel; pathogen; pathogenic bacteria; resistance mechanism; screening; small molecule libraries; synergism; wound; wound biofilm

Abstract/Project Summary The CDC reported that in 2019, 2.8 million infections due to antibiotic resistant bacteria occurred in the US, causing over 35,000 deaths. Bacterial biofilms are responsible for many of these infections, as biofilms confer resistance to multiple antibiotics via nonspecific factors such as exclusion of the drug and altered bacterial metabolism. Multidrug resistant Pseudomonas aeruginosa, a strong biofilm-forming pathogen, was responsible for 32,000 infections and 2,700 deaths in 2019. Most of these infections are associated with biofilms, and P. aeruginosa displays the nonspecific antibiotic resistance conferred by the complex biofilm it forms. To combat the increasing threat of this pathogen innovative intervention strategies must be designed. One of these strategies is synergy with currently used antibiotics. We employ high throughput screens (HTS) of chemical libraries and screening of complex plat products to identify synergistic compounds and substances that effectively eradicate preformed biofilms. A multistep HTS of over 6,000 synthetic compounds identified two promising candidates, triclosan (TRI) and oxyclozanide (OXY), that synergize with the antibiotic tobramycin (TOB) against established P. aeruginosa biofilms. Triclosan is a well-studied antimicrobial approved by the FDA. However it has not been studied for synergy with TOB. In addition, a screen of plant-derived substances identified Larrea tridentata and a component of Hydrastis canadensis as capable of eradicating preformed P. aeruginosa biofilms. Berberine (BER), a compound made by Hydrastis, inhibited P. aeruginosa biofilms in our assays and has previously been shown to synergize with TOB. We propose to test this synergy in a biofilm wound infection model, which has not been done. We have now shown that extracts of Larrea, which is also known as Creosote (CRE), are highly active against established P. aeruginosa biofilms, and we have shown this extract to be effective in a murine biofilm wound model of P. aeruginosa infection. This model is based on in vivo bioluminescence imaging (BLI), which greatly speeds the process of in vivo testing of biofilm infection in animals. Bioluminescent P. aeruginosa form a biofilm on the underside of a scab over the wound, allowing quantification of the infection in individual animals over time by non-invasive imaging. Here, we propose to develop the treatments we have identified by testing TOB synergy of the compounds and extracts in the BLI wound model. This process will establish novel treatments for P. aeruginosa biofilm infections in a rapid and quantitative manner.

摘要/项目摘要 疾病预防控制中心（CDC 造成超过35,000人死亡。细菌生物膜对许多感染负责，因为生物膜 通过非特异性因素（例如排除药物并改变）对多种抗生素的抗性 细菌代谢。抗多药假单胞菌铜绿假单胞菌是一种强生生物膜的病原体，是 2019年造成32,000次感染和2,700人死亡。这些感染大多数与 生物膜和铜绿假单胞菌显示由复合物生物膜赋予的非特异性抗生素耐药性 它形成。应对这种病原体创新干预策略的日益威胁必须是 设计。这些策略之一是与当前使用的抗生素协同作用。我们使用高通量 化学库的屏幕（HT）和复杂平台筛选以识别协同作用 有效根除预制的生物膜的化合物和物质。超过6,000的多步hts 合成化合物确定了两个有前途的候选者三氯糖（TRI）和氧化苯胺（Oxy），即 与已建立的铜绿假单胞菌生物膜相结合的抗生素毒素（TOB）。 Triclosan是一个 FDA批准了良好的抗菌抗菌。但是，尚未研究与TOB协同作用。在 此外，鉴定出植物来源的植物衍生物质的屏幕和hydrastis的组成部分 加拿大人能够消除预先形成的铜绿假单胞菌生物膜。 Berberine（BER），一个化合物 由Hydrastis制成，在我们的测定中抑制了铜绿假单胞菌生物膜，以前已被证明 与TOB协同作用。我们建议在生物膜伤口感染模型中测试这种协同作用，但 完毕。现在，我们已经表明，Larrea的提取物（也称为Creosote（Cre））高度 活跃于已建立的铜绿假单胞菌生物膜，我们已经证明该提取物在鼠中有效 铜绿假单胞菌感染的生物膜伤口模型。该模型基于体内生物发光成像 （BLI），这大大加快了动物中生物膜感染的体内测试过程。生物发光P. 在伤口上的结ab的下侧形成生物膜，允许对感染进行定量 随着时间的流逝，通过非侵入性成像。在这里，我们建议开发我们的治疗方法 通过测试BLI伤口模型中化合物和提取物的TOB协同作用。这 过程将以快速和定量的方式为铜绿假单胞菌生物膜感染建立新的治疗方法。