School of Food Science & Nutrition, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, UK.
Scientific Computing Department, Science and Technology Facilities Council, Daresbury Laboratory, Keckwick Lane, Daresbury, Warrington, WA4 4AD, UK; Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, UK.
Bioorg Med Chem. 2022 Oct 15;72:116945. doi: 10.1016/j.bmc.2022.116945. Epub 2022 Jul 26.
Chronic mucoid P. aeruginosa cystic fibrosis (CF) lung infections are associated with the development of a biofilm composed of anionic acetylated exopolysaccharide (EPS) alginate, electrostatically stabilised by extracellular Ca ions. OligoG CF-5/20, a low molecular weight guluronate rich oligomer, is emerging as a novel therapeutic capable of disrupting mature P. aeruginosa biofilms. However, its method of therapeutic action on the mucoid biofilm EPS is not definitively known at a molecular level. This work, utilising molecular dynamics (MD) and Density-Functional Theory (DFT), has revealed that OligoG CF-5/20 interaction with the EPS is facilitated solely through bridging Ca ions, which are not liberated from their native EPS binding sites upon OligoG CF-5/20 dispersal, suggesting that OligoG CF-5/20 does not cause disruptions to mature P. aeruginosa biofilms through breaking EPS-Ca-EPS ionic cross-links. Rather it is likely that the therapeutic activity arises from sequestering free Ca ions and preventing further Ca induced EPS aggregation.
慢性粘液性铜绿假单胞菌囊性纤维化（CF）肺部感染与由带负电荷的乙酰化胞外多糖（EPS）藻酸盐组成的生物膜的发展有关，该生物膜由细胞外 Ca 离子静电稳定。寡糖 CF-5/20 是一种低分子量富含古洛糖酸盐的低聚物，作为一种新型治疗方法，能够破坏成熟的铜绿假单胞菌生物膜。然而，其在粘液生物膜 EPS 上的治疗作用的作用机制在分子水平上尚不清楚。本工作利用分子动力学（MD）和密度泛函理论（DFT），揭示了寡糖 CF-5/20 与 EPS 的相互作用仅通过桥接 Ca 离子来促进，寡糖 CF-5/20 分散时不会从其天然 EPS 结合位点释放 Ca 离子，这表明寡糖 CF-5/20 不会通过破坏 EPS-Ca-EPS 离子交联来破坏成熟的铜绿假单胞菌生物膜。相反，治疗活性可能源于螯合游离 Ca 离子并防止进一步的 Ca 诱导的 EPS 聚集。
