9i96

Publication Abstract from PubMed

The lipopolysaccharide (LPS) transport (Lpt) system in Gram-negative bacteria maintains the integrity of the asymmetric bacterial outer membrane (OM). LPS biogenesis systems are essential in most Gram-negative bacteria, with LptDE responsible for the delivery of LPS to the outer leaflet of the OM. As an externally accessible, essential protein, LptDE offers a promising target for inhibitor development without the need for cellular penetration. However, there are no direct inhibitors of E. coli LptDE, and drug discovery is made challenging since it is a membrane target without a conventional active site. Here, the bicycle phage display platform was used in combination with cryogenic-electron microscopy (cryo-EM) and surface plasmon resonance to identify and map bicyclic peptide binders to Shigella flexneri LptDE (SfLptDE). Four distinct epitopes with unique bicycle molecule binding motifs were identified across the SfLptD beta-barrel. This method represents a streamlined workflow for the identification and prioritization of hit molecules against LptDE.

High-Throughput Identification and Characterization of LptDE-Binding Bicycle Peptides Using Phage Display and Cryo-EM.,Allyjaun S, Dunbar E, Hardwick SW, Newell S, Holding F, Rowland CE, St Denis MA, Pellegrino S, Arruda Bezerra G, Bournakas N, Chirgadze DY, Cooper L, Paris G, Lewis N, Brown P, Skynner MJ, Dawson MJ, Beswick P, Hubbard J, van den Berg B, Newman H J Med Chem. 2025 Oct 6. doi: 10.1021/acs.jmedchem.5c00307. PMID:41048016^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.