Chemistry Department, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Institute of Molecular Systems Biology and Department of Health Sciences and Technology, ETH Zürich, Otto-Stern-Weg 3, 8093 Zürich, Switzerland.
Sci Adv. 2018 Nov 14;4(11):eaau2634. doi: 10.1126/sciadv.aau2634. eCollection 2018 Nov.
With the increasing resistance of many Gram-negative bacteria to existing classes of antibiotics, identifying new paradigms in antimicrobial discovery is an important research priority. Of special interest are the proteins required for the biogenesis of the asymmetric Gram-negative bacterial outer membrane (OM). Seven Lpt proteins (LptA to LptG) associate in most Gram-negative bacteria to form a macromolecular complex spanning the entire envelope, which transports lipopolysaccharide (LPS) molecules from their site of assembly at the inner membrane to the cell surface, powered by adenosine 5'-triphosphate hydrolysis in the cytoplasm. The periplasmic protein LptA comprises the protein bridge across the periplasm, which connects LptBFGC at the inner membrane to LptD/E anchored in the OM. We show here that the naturally occurring, insect-derived antimicrobial peptide thanatin targets LptA and LptD in the network of periplasmic protein-protein interactions required to assemble the Lpt complex, leading to the inhibition of LPS transport and OM biogenesis in .
随着许多革兰氏阴性菌对现有抗生素类别的耐药性不断增加，寻找新的抗菌药物研发范式是一个重要的研究重点。特别值得关注的是革兰氏阴性菌不对称外膜（OM）生物发生所需的蛋白质。在大多数革兰氏阴性菌中，有七种 Lpt 蛋白（LptA 到 LptG）相互作用形成一个横跨整个包膜的大分子复合物，该复合物利用细胞质中的三磷酸腺苷水解作用，将脂多糖（LPS）分子从其在内膜的组装位置运输到细胞表面。周质蛋白 LptA 构成了穿过周质的蛋白质桥，它将内膜上的 LptBFGC 与锚定在 OM 中的 LptD/E 连接起来。我们在这里表明，天然存在的、来源于昆虫的抗菌肽 thanatin 靶向 LptA 和 LptD，这是组装 Lpt 复合物所需的周质蛋白-蛋白相互作用网络中的关键靶点，导致 LPS 转运和 OM 生物发生的抑制。
