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

仅在2019年，抗生素耐药性(AMR)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，因为他们较少获得适当的医疗保健，更容易受到慢性感染。抗生素的开发没有跟上步伐：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。嵌入生物膜的细菌在生物和非生物表面定居，细菌在那里新陈代谢地适应环境压力，如抗生素和杀菌剂的毒性。在生物膜内，细菌可以交换遗传物质，例如更有效地授予AMR的基因，这使得它们对抗生素的抗药性通常是自由生活细菌的1000多倍。据估计，65%的医院感染和80%的传染病与生物膜有关。导尿管相关性尿路感染(UTI)是由生物被膜形成引起的疾病，约占医院尿路感染的75%，全球每年的成本估计为10亿美元。这些感染中的许多对慢性和免疫抑制患者是致命的。例如，由铜绿假单胞菌引起的生物膜相关并发症是全球70,000名囊性纤维化患者的重大负担，估计每年造成75亿美元的损失。目前还缺乏有效的抗生物被膜方法，迫切需要能够阻止生物被膜形成的新化合物。在我们对鱼类免疫的研究中，我们发现了鱼血中一种名为Bing的小蛋白质。Bing属于一类被称为抗菌肽(AMP)的生物活性化合物。与其他已知的AMPS相比，Bing具有更高的热稳定性，对哺乳动物细胞的毒性更低。我们观察到，Bing迅速抑制细菌的运动，并强烈减少参与生物被膜形成初期许多过程的基因的表达，如与细菌游泳、定向和分泌胞外聚合物能力相关的基因。Bing可能具有抑制生物被膜形成的作用。此外，Bing还抑制了与将药物输送出细菌细胞有关的基因的表达。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先导。在这个项目中，我们将探索Bing作为抗生物被膜药物在临床环境中的潜力。为了促进这一发现的潜在临床翻译，我们将测试Bing对两种临床重要细菌--铜绿假单胞菌和致尿路病原性大肠杆菌(UPEC)生物膜形成的影响。我们还将研究Bing是否可以单独或在其他抗生素或杀生剂的存在下，消除生物膜内的细菌。

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.