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Clearance Of Microbial Biofilms by Advancing diagnostics and Therapy

Periodic Reporting for period 2 - COMBAT (Clearance Of Microbial Biofilms by Advancing diagnostics and Therapy)

Reporting period: 2018-11-01 to 2020-04-30

Biofilm-associated infections affect millions of people and are a leading cause of death and disability. With progress of medical sciences, more and more indwelling devices for the purpose of medical treatments and foreign body implants are applied. Infection continues to be a major complication of their use. Many efforts to decrease the burden of biofilm-assciated infections have been made, however there is still no anti-biofilm compund in clinical use. In this project, we concentrate on enhancing the activity of common antibiotics. Many of today´s antibiotics are very effective in the treatment of bacterial infections. However, their use in the successful eradication of biofilm-associated infection relies on our ability to overcome biofilm tolerance. The objectives of this project were defined in order to obtain new knowledge on the mechanisms of biofilm tolerance of the gram-negative pathogen Pseudomonas aeruginosa in order to improve current diagnostics and to develop effective therapeutic intervention strategies for the control of biofilm-associated infections.
We have used extensive microbiological and bioinformatic expertise combined with access to genetic and phenotypic information of a high number (>400) of relevant biofilm-forming P. aeruginosa isolates to unlock the potential of microbial genomics. We found that biofilm tolerance is independent on the resistance profile under planktonic growth conditions, and independent on the structural properties of the biofilms. It rather seems that the metabolic status of biofilm-grown cells determine the tolerance phenotype. We identified a small molecule that interferes with bacterial metabolism. This molecule was able to revert the biofilm tolerance phenotype, so that biofilm-grown bacteria became accessible towards conventional antimicrobial therapy.
Our results imply that biofilm-grown bacteria avoid antibiotic killing and become tolerant by counteracting intracellular alkalization through the adaptation of metabolic and transport functions. The link of biofilm tolerance with bacterial metabolism is interesting and opens up unique and novel possibilities to fight biofilm tolerance. Abrogation of antibiotic tolerance by interfering with the cell’s bioenergetics promises to pave the way for successful eradication of biofilm-associated infections. In this context, we are currently working on repurposing of already approved drugs as biofilm-sensitizing agents. This has the potential to accelerate the introduction of new treatments for recalcitrant biofilm-associated infections into the clinic.