Bacterial Biofilm Formation Inhibitors: A Novel Approach to Combat Antimicrobial Resistance

Antimicrobial resistance is a major global public health problem, with an alarming increase in bacterial infections that cannot be treated with current chemotherapies. According to World Health Organization, at least 700,000 people die each year worldwide due to antibiotic-resistant infections, and recent estimates suggest that in 2019, 4.95 million deaths were related to antimicrobial resistance, and 1.27 million deaths were directly attributed to it. By 2050, WHO predicts that the number of human deaths due to bacterial infections could exceed 10 million per year. Developing novel treatments and alternative therapies to spare existing antibiotics is essential to address this emerging health crisis. To combat antimicrobial resistance, targeting the resistance mechanisms of pathogenic bacteria, such as biofilm production, is a strategy. Bacterial biofilms are clusters of bacteria surrounded by extracellular polymeric substances (EPS) that colonize various surfaces. The EPS matrix hinders penetration of antimicrobials, and dormant cells in the biofilm are highly resistant to traditional antibiotics, requiring much higher doses. Biofilms are commonly associated with diseases such as cystic fibrosis, ear and urinary infections, respiratory tract infections, diabetic ulcers, wounds and medical device associated infections that are exacerbated by biofilm formation. In 2008 it has been recognized that biofilm forming bacteria pose a serious threat to public health, causing 60% of chronic infections and 80% of persistent infections in patients. Biofilm formation involves five steps: attachment, irreversible colonization, proliferation, maturation, and dispersion. In the attachment step, planktonic cells attach to a surface through weak interactions. Irreversible colonization involves producing extracellular matrix components to anchor the cells to the surface. Proliferation, maturation, and dispersion steps involve the growth and multiplication of cells, the production of extracellular polymeric matrix, and the release of individual planktonic cells, respectively. Understanding these processes is important for developing strategies to combat biofilm-associated infections. To inhibit biofilm formation, strategies such as preventing bacteria from adhering to surfaces, disrupting bacterial communication, modifying pathwas of signalling molecules, and inhibiting or disrupting mature biofilms can be used. These approaches have shown positive results in reducing pathogens when used with traditional antibiotics. By disrupting the EPS matrix and preventing biofilm formation, the effectiveness of antibiotics can be improved and antibiotic resistance can be slowed. Targeting virulence of bacteria without killing them is another alternative treatment that can be explored. It is important to prioritize research on developing novel biofilm inhibition methods to fight antimicrobial resistance. The project aims to discover and develop novel small-molecule inhibitors of bacterial biofilm formation through a multidisciplinary approach. This includes identifying new biofilm inhibitors via high-throughput screening of UL Faculty of Pharmacy compound library and designing and synthesizing small-molecule conjugates of known antibacterial agents and biofilm inhibitors, followed by evaluation of the hits and synthesized compounds in a range of biochemical and biological assays. The ultimate goal is to develop optimal biofilm compounds through an iterative cycle of design, synthesis, and evaluation, which will be subsequently evaluated for efficacy in an appropriate animal models. The project addresses the urgent need for new antimicrobial compounds to alleviate the increasing threat of infections caused by multidrug-resistant and persistent bacteria.