Fighting antimicrobial resistant infections by high-throughput discovery of biofilm-disrupting agents and mechanisms (DISRUPT)
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, highthroughput screening and antibiotics/antibody research.
Our project involves a combination of stateof-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 characterise the mechanism of action of novel anti-biofilm agents.
- Morten Kjos, Norwegian University of Life Sciences, Norway (Coordinator)
- Jan-Willem Veening, University of Lausanne, Switzerland
- Athanasios Typas, European Molecular Biology Laboratory , Germany
- Christoph Merten, European Molecular Biology Laboratory , Germany
Antimicrobial resistance is a growing problem worldwide. Many bacterial infections are nowadays often difficult to treat due to increasing antimicrobial resistance. Infections are particularly problematic if they are associated with biofilms. Biofilms are structured communities of bacteria, which are attached to surfaces. Infections typically caused by biofilms are wound-infections and urinary tract infections. The surface-attached biofilms are held together by a slimy matrix of polysaccharides, lipids, DNA and proteins. The matrix protects the bacterial cells against antibiotics and adds to the already existing resistance, making the infection treatment highly problematic. Novel strategies to treat such infections are therefore critical.
In our project we focus on four bacteria which has been listed as high-priority pathogens by WHO. These are (1) uropathogenic E. coli (the major cause of urinary tract infections and catheher infections), (2) Pseudomonas aeruginosa (whose biofilms are associated with chronic infections in wounds or during cystic fibrosis), (3) Staphylococcus aureus (causing biofilm-associated chronic wound – and medical implant infections), and (4) Streptococcus pneumoniae (whose biofilms have been associated with middle-ear infections and pneumoniae).
The DISRUPT project aims to identify new strategies to treat biofilm-associated infections. By inhibiting bacterial biofilms, the chances of infections will be reduced, and this will also resensitize the bacteria to existing antibiotics. To do this, we are using state-of-the-art genetic technologies (transposon sequencing, CRISPR interference) combined with high-throughput screens (screen for chemicals and microfluidic antibody screens) to identify anti-biofilm agents and mechanisms. The methods and resources we develop will be available for researchers worldwide, and will positively impact a range of research project related to AMR pathogens.
- bioRxiv – June 2020. Harnessing CRISPR-Cas9 for genome editing in Streptococcus pneumoniae
- bioRxiv, 2020. Exploration of bacterial bottlenecks and Streptococcus pneumoniae pathogenesis by CRISPRi-seq
- Cell Host & Microbe, 2020. Exploration of Bacterial Bottlenecks and Streptococcus pneumoniae Pathogenesis by CRISPRi-Seq
- eLife, 2020. Unbiased homeologous recombination during pneumococcal transformation allows for multiple chromosomal integration events
- mBio Oct, 2020. A CozE Homolog Contributes to Cell Size Homeostasis of Streptococcus pneumoniae
- MicrobiologyOpen, 2020. Penicillin‐binding protein PBP2a provides variable levels of protection toward different β‐lactams in Staphylococcus aureus RN4220
- Nature Structural & Molecular Biology, 2020. Structure of a proton-dependent lipid transporter involved in lipoteichoic acids biosynthesis
- PNAS, 2020. Synthetic gene-regulatory networks in the opportunistic human pathogen Streptococcus pneumoniae
- bioRxiv, 2019. Spatio-temporal control of DNA replication by the pneumococcal cell cycle regulator CcrZ