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

为了躲避抗生素等抗菌药物的影响，细菌菌落将自己嵌入到一种称为生物膜的粘性细胞外基质中。这种生物膜由糖、DNA和细胞材料组成的复杂网络组成，在阻止药物进入和让细菌不受阻碍地繁衍方面非常有效。我们之前已经创建了大规模的铜绿假单胞菌生物膜的多糖(糖)成分的原子模型[1]，这是一种在囊性纤维化患者的肺部发现的常见且经常致命的感染。初步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，从而深入了解了为什么一些药物可能有效而另一些无效，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)能够穿透这种粘性基质，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)研究水如何渗透到生物膜结构中，以及水通道是如何创建的，并对小分子(配体)的进入做出响应。Ii)使用通道模型作为环境，对基于铜绿假单胞菌和常见革兰氏阴性细菌[2]产生的群体感应分子前体的化合物进行构效关系分析，以了解哪些结构会破坏完全形成的生物膜的稳定性。三)确定这些化合物的优先次序，并考虑它们的化学成分如何有助于将生物膜附着在其他重要生物材料(例如牙齿的矿物表面和医用材料的聚合物表面)的表面模型上。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，在改善牙齿健康方面，在更智能的医疗材料的设计中，例如容易获得生物膜生长并成为患者感染源的导管和牙线。(2021年)。粘液型铜绿假单胞菌胞外多糖对阳离子的络合作用。Doi.org/10.1371/Joural.pone.0257026[2]--霍奇金森等人(2010年)。喹诺酮类假单胞菌信号分子的构效关系分析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