Boes Adrien, Brunel Jean Michel, Derouaux Adeline, Kerff Frédéric, Bouhss Ahmed, Touze Thierry, Breukink Eefjan, Terrak Mohammed
InBioS-Centre d'Ingénierie des Protéines, Liège University, 4000 Liège, Belgium.
UMR_MD1, U-1261, Aix Marseille Univ, INSERM, SSA, MCT, 13385 Marseille, France.
Antibiotics (Basel). 2020 Jul 2;9(7):373. doi: 10.3390/antibiotics9070373.
Peptidoglycan (PG) is an essential polymer of the bacterial cell wall and a major antibacterial target. Its synthesis requires glycosyltransferase (GTase) and transpeptidase enzymes that, respectively, catalyze glycan chain elongation and their cross-linking to form the protective sacculus of the bacterial cell. The GTase domain of bifunctional penicillin-binding proteins (PBPs) of class A, such as PBP1b, belong to the GTase 51 family. These enzymes play an essential role in PG synthesis, and their specific inhibition by moenomycin was shown to lead to bacterial cell death. In this work, we report that the aminosterol squalamine and mimic compounds present an unexpected mode of action consisting in the inhibition of the GTase activity of the model enzyme PBP1b. In addition, selected compounds were able to specifically displace the lipid II from the active site in a fluorescence anisotropy assay, suggesting that they act as competitive inhibitors.
肽聚糖（PG）是细菌细胞壁的一种必需聚合物，也是主要的抗菌靶点。其合成需要糖基转移酶（GTase）和转肽酶，它们分别催化聚糖链的延长及其交联，以形成细菌细胞的保护性囊泡。A类双功能青霉素结合蛋白（PBPs）的GTase结构域，如PBP1b，属于GTase 51家族。这些酶在PG合成中起重要作用，并且已表明莫能菌素对它们的特异性抑制会导致细菌细胞死亡。在这项工作中，我们报告氨基甾醇鲨胺及其模拟化合物呈现出一种意想不到的作用模式，即抑制模型酶PBP1b的GTase活性。此外，在荧光各向异性测定中，选定的化合物能够特异性地将脂质II从活性位点置换出来，这表明它们作为竞争性抑制剂起作用。
