Bello-Madruga Roberto, Sandín Daniel, Valle Javier, Gómez Jordi, Comas Laura, Larrosa María Nieves, González-López Juan José, Jiménez María Ángeles, Andreu David, Torrent Marc
The Systems Biology of Infection Laboratory, Department of Biochemistry and Molecular Biology, Biosciences Faculty, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, 08193, Spain.
Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona Biomedical Research Park, Barcelona, 08003, Spain.
Mol Syst Biol. 2025 May 23. doi: 10.1038/s44320-025-00120-6.
Glycosaminoglycan (GAG)-binding proteins regulating essential processes such as cell growth and migration are essential for cell homeostasis. As both GAGs and the lipid A disaccharide core of Gram-negative bacteria contain negatively charged disaccharide units, we hypothesized that GAG-binding proteins could also recognize LPS and enclose cryptic antibiotic motifs. Here, we report novel antimicrobial peptides (AMPs) derived from heparin-binding proteins (HBPs), with specific activity against Gram-negative bacteria and high LPS binding. We used computational tools to locate antimicrobial regions in 82% of HBPs, most of those colocalizing with putative heparin-binding sites. To validate these results, we synthesized five candidates [HBP-1-5] that showed remarkable activity against Gram-negative bacteria, as well as a strong correlation between heparin and LPS binding. Structural characterization of these AMPs shows that heparin or LPS recognition promotes a conformational arrangement that favors binding. Among all analogs, HBP-5 displayed the highest affinity for both heparin and LPS, with antimicrobial activities against Gram-negative bacteria at the nanomolar range. These results suggest that GAG-binding proteins are involved in LPS recognition, which allows them to act also as antimicrobial proteins. Some of the peptides reported here, particularly HBP-5, constitute a new class of AMPs with specific activity against Gram-negative bacteria.
调节细胞生长和迁移等基本过程的糖胺聚糖（GAG）结合蛋白对细胞稳态至关重要。由于GAG和革兰氏阴性菌的脂质A二糖核心都含有带负电荷的二糖单元，我们推测GAG结合蛋白也可能识别脂多糖（LPS）并包裹隐藏的抗生素基序。在此，我们报告了源自肝素结合蛋白（HBP）的新型抗菌肽（AMP），它们对革兰氏阴性菌具有特异性活性且与LPS有高结合力。我们使用计算工具在82%的HBP中定位抗菌区域，其中大多数与假定的肝素结合位点共定位。为验证这些结果，我们合成了五种候选物[HBP - 1 - 5]，它们对革兰氏阴性菌显示出显著活性，并且肝素与LPS结合之间存在很强的相关性。这些AMP的结构表征表明，肝素或LPS识别促进了有利于结合的构象排列。在所有类似物中，HBP - 5对肝素和LPS都表现出最高亲和力，在纳摩尔范围内对革兰氏阴性菌具有抗菌活性。这些结果表明，GAG结合蛋白参与LPS识别，这使它们也能作为抗菌蛋白发挥作用。本文报道的一些肽，特别是HBP - 5，构成了一类对革兰氏阴性菌具有特异性活性的新型AMP。
