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

点击翻译按钮获取中文摘要

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.