Computational modelling of bacterial biofilm permeability and the design of novel antimicrobial therapeutics

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To evade the effects of antimicrobial drugs, such as antibiotics, colonies of bacteria embed themselves in a sticky extracellular matrix, called a biofilm. Composed of a complex network of sugars, DNA and cellular material, the biofilm is highly effective at keeping drugs out and allowing the bacteria to thrive unhindered. We have previously created large-scale atomic models of the polysaccharide (sugar) component of the Pseudomonas aeruginosa biofilm [1], which is a common and frequently fatal infection found within the lungs of cystic fibrosis sufferers. Initial molecular dynamic simulations have revealed the way the biofilm can either capture (bind) or aid the passage of a variety of small molecules, providing insight into why some drugs may be effective and others not, and why quorum sensing molecules (the metabolic messages bacteria send to each other e.g. PQS) can penetrate this sticky matrix and disperse freely between different bacterial colonies. In this project, we will take this modelling further and perform the following steps.i) Investigate how water permeates the biofilm structure and how water channels are created and respond to the ingress of small molecules (ligands). ii) Use the channel models as environments to perform structure-activity relationship analysis of compounds based on quorum sensing molecule precursors made by P. aeruginosa and common Gram-negative bacteria[2], to understand which structures destabilise the fully formed biofilm. iii) Prioritize these compounds and consider how their chemistry contributes to the attachment of biofilms to surface models of other important biological materials (e.g. mineral surfaces of teeth and polymer surfaces of medical materials). The impact of this work will be felt in many areas, for example, in the treatment of diseases such as cystic fibrosis, in the improvement of dental health, and in the design of smarter medical materials such as catheter and dental lines that are prone to acquiring biofilm growth and becoming sources of patient infection.[1] - Hills et al. (2021). Cation complexation by mucoid Pseudomonas aeruginosa extracellular polysaccharide. doi.org/10.1371/journal.pone.0257026[2] - Hodgkinson et al (2010). Structure-Activity Analysis of the Pseudomonas Quinolone Signal Molecule. doi:10.1128/JB.00081-10