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

为了逃避抗生素等抗微生物药物的影响，细菌菌落将自己嵌入一种称为生物膜的粘性细胞外基质中。生物膜由糖、DNA和细胞物质组成的复杂网络组成，在阻止药物进入和允许细菌不受阻碍地生长方面非常有效。我们之前已经创建了铜绿假单胞菌生物膜的多糖（糖）成分的大规模原子模型[1]，这是囊性纤维化患者肺部发现的一种常见且经常致命的感染。最初的分子动力学模拟揭示了生物膜可以捕获（结合）或帮助各种小分子通过的方式，从而深入了解为什么某些药物可能有效而其他药物无效，以及为什么群体感应分子（细菌相互发送的代谢信息，例如PQS）可以穿透这种粘性基质并在不同的细菌菌落之间自由分散。在这个项目中，我们将进一步进行建模，并执行以下步骤：i）研究水如何渗透生物膜结构，以及水通道如何创建和响应小分子（配体）的进入。ii）使用通道模型作为环境，对基于由铜绿假单胞菌和常见革兰氏阴性菌产生的群体感应分子前体的化合物进行结构-活性关系分析[2]，以了解哪些结构使完全形成的生物膜不稳定。iii）优先考虑这些化合物，并考虑它们的化学性质如何有助于生物膜附着在其他重要生物材料的表面模型上（例如牙齿的矿物表面和医疗材料的聚合物表面）。这项工作的影响将在许多领域感受到，例如，在囊性纤维化等疾病的治疗中，在牙齿健康的改善中，以及在更智能的医疗材料的设计中，例如导管和牙科线，这些材料易于获得生物膜生长并成为患者感染的来源。[1]- Hills et al.（2021）.粘液型铜绿假单胞菌胞外多糖的阳离子络合作用。doi.org/10.1371/journal.pone.0257026[2] - Hodgkinson等人（2010）。喹诺酮类假单胞菌信号分子的结构-活性分析。doi：10.1128/JB.00081-10

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