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JPIAMR-JPI Antimikrobiell resistens

Fighting antimicrobial resistant infections by high-throughput discovery of biofilm-disrupting agents and mechanisms

Alternative title: Identifisering av nye anti-biofilm mekanismar for å motverke antibiotikaresistente infeksjonar

Awarded: NOK 4.5 mill.

Antimicrobial resistance is a growing problem worldwide. Many bacterial infections are nowadays often difficult to treat due to increasing antimicrobial resistance. Novel research tools are critical for the research community to find new strategies to fight infections cause by antibiotic resistant bacteria. In the DISRUPT-project we have focused on different priority pathogens (as defined by WHO), and particularly on pathogens causing biofilm-associated infections. These include uropathogenic E. coli (the major cause of urinary tract infections and catheter infections), Staphylococcus aureus (causing biofilm-associated chronic wound - and medical implant infections), and Streptococcus pneumoniae (whose biofilms have been associated with middle-ear infections and pneumoniae). Biofilms are structured communities of bacteria which are attached to surfaces via a slimy matrix, and these biofilms make the pathogens extra resistant towards antibiotics and adds to the already existing resistance, making the infection treatment highly problematic. During the project period we have constructed a set of novel, cutting-edge research tools for these pathogens. We have generated genome-wide mutant libraries based on transposon mutagenesis and CRISRP interference technologies, and made methods which allows for robotic-based screens for antibacterial and antibiofilm compounds. Furthermore, we have set up a novel microfluidic-based technology which allows for screening of antibacterial antibodies in droplets. In the frame of this project, our novel tools have allowed for high-throughput screens to identify which genes that are essential for growth and biofilm formation in these bacteria, as well as to identify novel antibacterial antibodies. The approaches developed here will be highly valuable as tools researchers working on these AMR pathogens beyond the current project.

Through the DISRUPT project, three PhD-students and two postdoctoral researchers in Norway, Germany and Switzerland have performed their training. Two other PhD-students who were not employed in the project, participated in the project tasks, as well as several master received their training as part of the project. All the researchers as well as the labs involved have expanded their international network via this project. In addition to the specific results obtained, a number of research tools and resources have been generated through this project (including methods for screening of antibacterial antibodies, genome-wide mutant libraries, new protocols for robotics setup, analysis tools for genome-wide screens, protocol for CRISPRi-Seq) and all these will be of major importance for future research projects on the AMR pathogens E. coli, S. aureus and S. pneumoniae.

Many bacterial infections are associated with biofilms. Biofilm-related infections, particularly those caused by drug resistant bacteria, are difficult to handle with current antibiotic strategies. This includes wound-infections (e.g. caused by Pseudomonas aeruginosa or Staphylococcus aureus), urinary tract infections (e.g. Escherichia coli), chronic airway infections (e.g. P. aeruginosa) and pre-infection colonization by Streptococcus pneumoniae. New strategies and compounds to fight such resilient infections are imperative; however, the full repertoire of genes and processes that are essential for biofilm formation in different microbes is unknown. In this project, we aim to provide new tools, targets and agents for understanding and treating biofilm-associated infections in four major AMR pathogens (P. aeruginosa, UPEC, S. aureus and S. pneumoniae). To achieve this, we have assembled an interdisciplinary team with diverse expertise in microbial genetics and genomics, high-throughput screening and antibiotics/antibody research. Our project involves a combination of state-of-the-art genetic approaches to construct genome-wide tools with automated biofilm-phenotyping and high-throughput screening for anti-biofilm antibodies and chemicals. Finally, we will characterize the mechanism of action of novel anti-biofilm agents.

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JPIAMR-JPI Antimikrobiell resistens