University Centre Varaždin, University North, 104. Brigade 3, 42 000 Varaždin, Croatia.
Clinical Microbiology and Parasitology Unit, Polyclinic "Dr. Zora Profozić", Bosutska 19, 10 000 Zagreb, Croatia.
Med Hypotheses. 2019 Mar;124:17-20. doi: 10.1016/j.mehy.2019.01.010. Epub 2019 Jan 11.
Urinary tract infections are among the most common infectious diseases worldwide, primarily caused by uropathogenic Escherichia coli (UPEC) strains that harbor type I pili and P pili on the surface. Standard E. coli therapy still entails antibiotic consumption, but urinary tract infections tend to recur at a very high rate. Due to the emergence of antibiotic resistant strains of UPEC, as well as high infection recurrence rates, there is a need for new approaches to efficiently treat and prevent urinary tract infections. Since aforementioned adhesive organelles are the principal virulence factors in UPEC, anti-adhesion strategy seems to be the most promising (and hitherto unexplored) treatment option. Here we propose an antiadhesive dual targeting approach towards FimH and PapG adhesive proteins placed on two key virulence factors for UPEC - type I fimbriae and P pili. Such dual antagonists will contain appropriate pharmacophores (mannose and natural cranberry-containing polyphenol) joined together and will more efficiently block the infection and prevent the progression of the disease in comparison to FimH and PapG as isolated targets. More specifically, polyphenol mannosides (due to the structural similarities with the most potent biaryl inhibitors) can act as high-affinity FimH ligands, while cranberry-associated polyphenol moiety can additionally inhibit the PapG-mediated adhesion. Proposed compound may also contribute to the antioxidant capacity of the human organism. In conclusion, this dual-target hypothesis for the prevention and treatment of UPEC infections represents an important foundation for further research on this topic.
尿路感染是全球最常见的传染病之一，主要由尿路致病性大肠杆菌（UPEC）菌株引起，这些菌株在表面携带 I 型菌毛和 P 菌毛。标准的大肠杆菌治疗仍然需要抗生素的消耗，但尿路感染往往会以非常高的复发率出现。由于 UPEC 抗药性菌株的出现以及高感染复发率，因此需要新的方法来有效治疗和预防尿路感染。由于上述粘附细胞器是 UPEC 主要的毒力因子，因此抗粘附策略似乎是最有前途的（迄今尚未探索）治疗选择。在这里，我们提出了一种针对 FimH 和 PapG 粘附蛋白的双靶向抗粘附方法，这两种蛋白位于 UPEC 的两种关键毒力因子——I 型菌毛和 P 菌毛上。与作为孤立靶点的 FimH 和 PapG 相比，这种双重拮抗剂将包含适当的药效团（甘露糖和含有天然蔓越莓的多酚），并更有效地阻断感染并防止疾病的进展。更具体地说，多酚甘露糖苷（由于与最有效的联苯抑制剂具有结构相似性）可以作为高亲和力的 FimH 配体，而蔓越莓相关的多酚部分还可以抑制 PapG 介导的粘附。所提出的化合物还可能有助于提高人体的抗氧化能力。总之，这种针对 UPEC 感染的预防和治疗的双靶标假说代表了该主题进一步研究的重要基础。
