Discovery of N‑β‑l‑Fucosyl Amides as High-Affinity Ligands for the Pseudomonas aeruginosa Lectin LecB

The Gram-negative pathogen Pseudomonas aeruginosa causes severe infections mainly in immunocompromised or cystic fibrosis patients and is able to resist antimicrobial treatments. The extracellular lectin LecB plays a key role in bacterial adhesion to the host and biofilm formation. For the inhibition of LecB, we designed and synthesized a set of fucosyl amides, sulfonamides, and thiourea derivatives. Then, we analyzed their binding to LecB in competitive and direct binding assays. We identified β-fucosyl amides as unprecedented high-affinity ligands in the two-digit nanomolar range. X-ray crystallography of one α- and one β-anomer of N-fucosyl amides in complex with LecB revealed the interactions responsible for the high affinity of the β-anomer at atomic level. Further, the molecules showed good stability in murine and human blood plasma and hepatic metabolism, providing a basis for future development into antibacterial drugs.

革兰氏阴性病原菌铜绿假单胞菌（Pseudomonas aeruginosa）主要感染免疫功能低下或囊性纤维化患者，可引发重症感染，且能耐受抗菌治疗。该菌的细胞外凝集素LecB在细菌黏附宿主及生物被膜形成过程中发挥关键作用。为抑制LecB的活性，本研究设计并合成了一系列岩藻糖基酰胺（fucosyl amides）、磺酰胺（sulfonamides）及硫脲衍生物（thiourea derivatives）；随后通过竞争性结合实验与直接结合实验，分析了这些化合物与LecB的结合活性。研究鉴定出β-岩藻糖基酰胺为前所未有的高亲和力配体，其亲和力处于两位数纳摩尔级别。通过解析N-岩藻糖基酰胺的α、β端基异构体与LecB形成复合物的X射线晶体学（X-ray crystallography）结构，本研究在原子层面揭示了β异构体高亲和力的相互作用机制。此外，该类化合物在小鼠及人血浆中表现出良好稳定性，且肝脏代谢特性优异，为后续开发抗菌药物奠定了重要基础。