Breaking down the city walls: small molecules that target bacterial biofilms


Although bacteria are single celled organisms, they are capable of working together in massive bacterial colonies known as biofilms. Within the biofilm bacteria will differentiate to perform different tasks, all wrapped up within a sticky substance that holds the cells together. I’ve written about biofilms before; how they form and how they work in space!
Biofilms form on surfaces where bacteria gather including body surfaces and medical equipment. They are incredibly hard to get rid of. Antibiotics can’t penetrate down to the lower levels of the biofilm at high enough concentrations to kill, and the presence of low-level antibiotics encourages the development of antibiotic resistance. There is therefore a lot of research into biofilms, and particularly into treatments that can destroy them, or prevent them from forming.
Polymicrobic biofilm grown on a stainless steel surface, stained with 4,6-diamidino-2-phenylindole (DAPI) and examined by epifluorescence microscopy. Bar, 20 µm. Ricardo Murga and Rodney M. Donlan: "Biofilms: Microbial Life on Surfaces"
A recent article in PLoS Pathogens looks at the possibility of removing biofilms by knocking out small signalling molecules. These signalling molecules regulate a number of genes involved in biofilm formation and are strongly evolutionarily conserved, meaning they are found in a wide range of bacteria. This means that a treatment based on targeting them would potentially work across a broad spectrum of both Gram negative and Gram positive bacteria.
The peptide they studied was labelled 1018 and was found to prevent biofilm formation and kill established biofilms at low concentrations that had no effect on the planktonic free-living bacteria. Low levels of the peptide lead to the biofilm breaking up and dispersing while higher levels caused cell death within the biofilm.
The image above shows the results: displayed graphically above and pictorially below. On the left, the live cell counts under normal conditions, after 0, 3 and 23 hours. The cell count is increasing as the biofilm develops. The image shows the mushroom shape of the biofilm forming. In the middle is the result of cell growth in the presence of low levels of 1018 (0.8 µg/ml). The cells are growing, but the biofilm has been split up and scattered, with only free-living platonic cells left behind. To the right, is the result of cell growth in the presence of high levels of 1018 (10 µg/ml). In this case the cells are killed and no biofilm grows.
Excitingly, this result was repeated over different species of bacteria, showing broad-spectrum activity. Further investigation into 1018 showed it was able to bind to the small signalling molecules. Exactly how it binds to the signalling molecule, and what is does with it after binding, is still uncertain. As is the precise role of the small signalling molecules in the formation of biofilms. While this is medically interesting there are still a lot of unanswered biochemical questions!
What has been shown is that 1018 has three main effects. Firstly it prevents biofilm formation when added to free-living cells. Secondly it breaks up biofilms at low concentrations, and thirdly it can break up and disperse even 2 day old biofilms. Even if only used at low concentrations, this would be a highly medically useful molecule, breaking up biofilms leaving bacterial cells more susceptible to antibiotics and other anti-microbial agents.
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Reference: de la Fuente-Núñez C, Reffuveille F, Haney EF, Straus SK, Hancock REW (2014) Broad-Spectrum Anti-biofilm Peptide That Targets a Cellular Stress Response. PLoS Pathog 10(5): e1004152.

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