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

Antimicrobial resistance is a growing problem worldwide. An increasing number of infections are difficult to treat as a result of AMR pathogens such as staphylococci, pneumococci, E. coli and Pseudomonas. Infections caused by AMR pathogens are particularly difficult to treat if they are associated with biofilms. Infections typically caused by biofilms are wound-infections and urinary tract infections. Biofilms are structured, surface-attached communities of bacteria. The surface-attached biofilms are held together by a slimy matrix of polysaccharides, lipids, DNA and proteins. The matrix protects the bacterial cells and adds to the resistance, making the infection treatment highly problematic. Novel strategies to treat such infections are therefore critical. Targeting and inhibiting bacterial biofilm formation will reduce the chances of infections, and possibly sensitize the bacteria to other antibiotics or the immune system. DISRUPT, which is a collaborative project between research groups in Norway (at NMBU), Switzerland and Germany, aims to identify new strategies to treat biofilm-associated infections caused by staphylococci, pneumococci, E. coli and Pseudomonas. In this project, we have so far developed CRISPR interference genome-wide libraries as well as transposon mutagenesis libraries in Staphylococcus aureus strains. Both pooled and arrayed libraries will be published and made available as novel and useful genetic resources for the research community. We have used the libraries to determine how S. aureus survive and proliferate in different conditions as well as to screen for novel anti-biofilm targets and strategies. We have identified multiple novel mechanisms involved in biofilm formation/surface attachment and structuring. These include metabolic proteins which have major influence on biofilm formation in staphylococci, as well as extracellular, cell-wall degrading hydrolases. The potential of these to act as novel targets to inhibit staphylococcal biofilms is currently under investigation.

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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.

Publications from Cristin

SmdA is a Novel Cell Morphology Determinant in Staphylococcus aureus

The cell cycle of Staphylococcus aureus: An updated review

Ubericin K, a New Pore-Forming Bacteriocin Targeting mannose-PTS

Penicillin-binding protein PBP2a provides variable levels of protection towards different β-lactams in Staphylococcus aureus RN4220

A CozE Homolog Contributes to Cell Size Homeostasis of Streptococcus pneumoniae

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SAOUHSC_00671 contributes to cell splitting and biofilm formation in Staphylococcus aureus and its expression is associated with other peptidoglycan hydrolases

Uncovering novel mechanisms of controlling LTA biosynthesis in Staphyloccoccus aureus

CRISPR som verktøy for genredigering og genregulering i bakterier

Antibiotic susceptibility screens by CRISPRi in Staphylococcus aureus

Identification and characterization of a novel staphylococcal cell morphology determinant

The transcription of Staphylococcus aureus peptidoglycan hydrolases is interconnected

Elucidating genetic factors of Staphylococcus aureus bovine mastitis

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