A novel anti-biofilm peptide from fish for the combat against antimicrobial resistance

一种来自鱼类的新型抗生物膜肽，用于对抗抗菌素耐药性

• 批准号: MR/Y503393/1
• 负责人: Yun Wah Lam
• 金额: $ 19.87万
• 依托单位: University of Huddersfield
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY503393%2F1
• 关键词: novel; anti; biofilm; peptide; fish

In 2019 alone, antibiotic resistance (AMR) directly caused an estimated 1.2 million deaths worldwide. This number is predicted to increase to 10 million in 2050. Underprivileged populations are particularly vulnerable, as they have less access to proper healthcare and are more prone to chronic infections. Antibiotic development is not keeping up: only 18 new antibiotics have been approved by the FDA since 2010; most of them are modifications to existing ones rather than new drug classes. Most bacteria have two different lifestyles. They can live as free-living organisms or clumped inside a structure called biofilm. Biofilm is a physiochemical barrier that shields bacterial cells from harsh environmental conditions. Biofilm-embedded bacteria colonise biotic and abiotic surfaces, where bacteria are metabolically adapted to environmental stresses such as toxicities from antibiotics and biocides. Inside biofilms, bacteria can exchange genetic materials, such as genes that confer AMR more effectively, making them typically over 1000 times more resistant to antibiotics than free-living bacteria. Biofilms are estimated to be involved in?~?65% of hospital infections and ~80% of all infectious diseases. Catheter-associated urinary tract infections (UTI), conditions caused by biofilm formation, account for ~75% of UTIs in hospitals, with an estimated global cost of US$1bn annually. Many of these infections are fatal to chronic and immunosuppressed patients. E.g., biofilm-related complications caused by the bacteria P. aeruginosa are a significant burden on the >70,000 cystic fibrosis patients worldwide, costing an estimated US$7.5 billion annually. There is a desperate shortage of effective anti-biofilm methods, and new compounds that can hinder biofilm formation are urgently needed. During our research on fish immunity, we discovered a small protein known as BING in fish blood. BING belongs to a class of bioactive compounds called antimicrobial peptides (AMP). Compared to other known AMPs, BING is much more heat stable and has a lower toxicity towards mammalian cells. We observed that BING rapidly inhibits bacterial motility and strongly reduces the expression of genes involved in many processes in the initial phase of biofilm formation, such as genes related to the ability of bacteria to swim, orient, and to secrete extracellular polymers. It is possible that BING can inhibit biofilm formation. In addition, BING suppresses the expression of genes involved in pumping drugs out of the bacterial cells. Hence, BING appears to simultaneously hit multiple mechanisms that cause AMR, making it a highly attractive therapeutic lead.In this project, we will explore the potential of BING as an anti-biofilm agent in clinical settings. To facilitate the potential clinical translation of this discovery, we will test the effect of BING on biofilm formation of two clinically important bacteria, P. aeruginosa and uropathogenic E. coli (UPEC). We will also study whether BING, on its own or in the presence of other antibiotics or biocides, can eliminate the bacteria living inside biofilms.

仅 2019 年，抗生素耐药性 (AMR) 就直接导致全球约 120 万人死亡。预计到 2050 年，这一数字将增加到 1000 万。贫困人口尤其脆弱，因为他们获得适当医疗保健的机会较少，并且更容易患慢性感染。抗生素开发跟不上：自2010年以来，FDA仅批准了18种新抗生素；其中大多数是对现有药物的修改，而不是新的药物类别。大多数细菌有两种不同的生活方式。它们可以作为自由生物体生活，也可以聚集在称为生物膜的结构内。生物膜是一种物理化学屏障，可以保护细菌细胞免受恶劣环境条件的影响。生物膜嵌入的细菌定植于生物和非生物表面，细菌在这些表面上通过代谢适应环境压力，例如抗生素和杀菌剂的毒性。在生物膜内部，细菌可以交换遗传物质，例如更有效地赋予 AMR 的基因，这使得它们对抗生素的抵抗力通常比自由生活的细菌高 1000 倍以上。据估计，生物膜与约 65% 的医院感染和约 80% 的所有传染病有关。导管相关性尿路感染 (UTI) 是由生物膜形成引起的疾病，约占医院尿路感染的 75%，估计全球每年造成 10 亿美元的损失。其中许多感染对于慢性病和免疫抑制患者来说是致命的。例如，由铜绿假单胞菌引起的生物膜相关并发症给全球超过 70,000 名囊性纤维化患者带来了沉重负担，每年造成的损失估计达 75 亿美元。目前非常缺乏有效的抗生物膜方法，迫切需要能够阻碍生物膜形成的新化合物。在对鱼类免疫力的研究中，我们在鱼的血液中发现了一种称为 BING 的小蛋白质。 BING 属于一类称为抗菌肽 (AMP) 的生物活性化合物。与其他已知的 AMP 相比，BING 具有更高的热稳定性，并且对哺乳动物细胞的毒性更低。我们观察到，BING 快速抑制细菌运动，并强烈降低生物膜形成初始阶段涉及许多过程的基因的表达，例如与细菌游泳、定向和分泌细胞外聚合物的能力相关的基因。 BING 可能会抑制生物膜的形成。此外，BING 还能抑制与将药物从细菌细胞中泵出有关的基因的表达。因此，BING 似乎同时作用于导致 AMR 的多种机制，使其成为极具吸引力的治疗先导药物。在这个项目中，我们将探索 BING 作为临床环境中抗生物膜剂的潜力。为了促进这一发现的潜在临床转化，我们将测试 BING 对两种临床重要细菌——铜绿假单胞菌和尿路致病性大肠杆菌 (UPEC) 生物膜形成的影响。我们还将研究 BING 单独使用或与其他抗生素或杀菌剂一起使用是否可以消除生物膜内的细菌。