Targeting the Central Pocket of the Pseudomonas aeruginosa Lectin LecA
Issued Date
2022-02-04
Resource Type
ISSN
14394227
eISSN
14397633
Scopus ID
2-s2.0-85120415679
Pubmed ID
34788491
Journal Title
ChemBioChem
Volume
23
Issue
3
Rights Holder(s)
SCOPUS
Bibliographic Citation
ChemBioChem Vol.23 No.3 (2022)
Suggested Citation
Siebs E., Shanina E., Kuhaudomlarp S., da Silva Figueiredo Celestino Gomes P., Fortin C., Seeberger P.H., Rognan D., Rademacher C., Imberty A., Titz A. Targeting the Central Pocket of the Pseudomonas aeruginosa Lectin LecA. ChemBioChem Vol.23 No.3 (2022). doi:10.1002/cbic.202100563 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/84208
Title
Targeting the Central Pocket of the Pseudomonas aeruginosa Lectin LecA
Author's Affiliation
Laboratoire d'Innovation Thérapeutique (LIT)
Universität des Saarlandes
Freie Universität Berlin
Universität Wien
Max Perutz Labs
Mahidol University
Helmholtz Centre for Infection Research (HZI)
Max-Planck-Institut für Kolloid- und Grenzflächenforschung
Centre de Recherches sur les Macromolécules Végétales
Deutsches Zentrum für Infektionsforschung (DZIF)
Universität des Saarlandes
Freie Universität Berlin
Universität Wien
Max Perutz Labs
Mahidol University
Helmholtz Centre for Infection Research (HZI)
Max-Planck-Institut für Kolloid- und Grenzflächenforschung
Centre de Recherches sur les Macromolécules Végétales
Deutsches Zentrum für Infektionsforschung (DZIF)
Other Contributor(s)
Abstract
Pseudomonas aeruginosa is an opportunistic ESKAPE pathogen that produces two lectins, LecA and LecB, as part of its large arsenal of virulence factors. Both carbohydrate-binding proteins are central to the initial and later persistent infection processes, i. e. bacterial adhesion and biofilm formation. The biofilm matrix is a major resistance determinant and protects the bacteria against external threats such as the host immune system or antibiotic treatment. Therefore, the development of drugs against the P. aeruginosa biofilm is of particular interest to restore efficacy of antimicrobials. Carbohydrate-based inhibitors for LecA and LecB were previously shown to efficiently reduce biofilm formations. Here, we report a new approach for inhibiting LecA with synthetic molecules bridging the established carbohydrate-binding site and a central cavity located between two LecA protomers of the lectin tetramer. Inspired by in silico design, we synthesized various galactosidic LecA inhibitors with aromatic moieties targeting this central pocket. These compounds reached low micromolar affinities, validated in different biophysical assays. Finally, X-ray diffraction analysis revealed the interactions of this compound class with LecA. This new mode of action paves the way to a novel route towards inhibition of P. aeruginosa biofilms.