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.

仅在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。贫困人口特别脆弱，因为他们获得适当医疗保健的机会较少，更容易受到慢性感染。抗生素的发展并没有跟上：自2010年以来，FDA只批准了18种新的抗生素;其中大多数是对现有抗生素的修改，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活的有机体生活，也可以聚集在一种称为生物膜的结构中。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。生物膜包埋的细菌定植在生物和非生物表面，其中细菌在代谢上适应环境压力，例如抗生素和杀生物剂的毒性。在生物膜内，细菌可以交换遗传物质，例如更有效地赋予AMR的基因，使它们对抗生素的抗性通常比自由生活的细菌高1000倍以上。生物膜可能参与了？~？医院感染的65%和所有传染病的~80%。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UTI的75%，估计全球每年的费用为10亿美元。许多这些感染是致命的慢性和免疫抑制患者。例如，在一个示例中，由细菌铜绿假单胞菌引起的生物膜相关并发症是全世界超过70，000名囊性纤维化患者的重大负担，估计每年花费75亿美元。有效的抗生物膜方法严重短缺，迫切需要能够阻碍生物膜形成的新化合物。在我们对鱼类免疫力的研究中，我们在鱼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热稳定性更好，对哺乳动物细胞的毒性更低。我们观察到，BING快速抑制细菌运动性，并强烈降低生物膜形成的初始阶段中参与许多过程的基因的表达，例如与细菌游泳，定向和分泌胞外聚合物的能力相关的基因。BING有可能抑制生物膜的形成。此外，BING抑制了参与将药物从细菌细胞中泵出的基因的表达。因此，BING似乎同时击中了导致AMR的多种机制，使其成为一个非常有吸引力的治疗lead.In本项目中，我们将探索BING作为抗生物膜剂在临床环境中的潜力。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生物膜形成的影响。大肠杆菌（UPEC）。我们还将研究BING本身或在其他抗生素或杀生物剂的存在下是否可以消除生活在生物膜内的细菌。