Targeting the Central Pocket of the Pseudomonas aeruginosa Lectin LecA

Christoph Johannes Heinrich Rademacher, Eike Siebs, Elena Shanina, Sakonwan Kuhaudomlarp, Priscila da Silva Figueiredo Celestino Gomes, Cloé Fortin, Peter H. Seeberger, Didier Rognan, Anne Imberty, Alexander Titz (Korresp. Autor*in)

Veröffentlichungen: Beitrag in FachzeitschriftArtikelPeer Reviewed

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.

OriginalspracheEnglisch
Aufsatznummere202100563
Seitenumfang9
FachzeitschriftChemBioChem: a european journal of chemical biology
Jahrgang23
Ausgabenummer3
Frühes Online-Datum17 Nov. 2021
DOIs
PublikationsstatusVeröffentlicht - 4 Feb. 2022

ÖFOS 2012

  • 301207 Pharmazeutische Chemie

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