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[4.3.1]Bicyclic FKBP ligands inhibit Legionella Pneumophila infection by LpMip‐dependent and LpMip‐independent mechanisms

Deutscher, Robin C. E. ; Safa Karagöz, M. ; Purder, Patrick L. ; Kolos, Jürgen M. ; Meyners, Christian ; Oki Sugiarto, Wisely ; Krajczy, Patryk ; Tebbe, Frederike ; Geiger, Thomas M. ; Ünal, Can ; Hellmich, Ute A. ; Steinert, Michael ; Hausch, Felix (2023)
[4.3.1]Bicyclic FKBP ligands inhibit Legionella Pneumophila infection by LpMip‐dependent and LpMip‐independent mechanisms.
In: ChemBioChem, 24 (21)
doi: 10.1002/cbic.202300442
Article, Bibliographie

This is the latest version of this item.

Abstract

Legionella pneumophila is the causative agent of Legionnaires’ disease, a serious form of pneumonia. Its macrophage infectivity potentiator (Mip), a member of a highly conserved family of FK506‐binding proteins (FKBPs), plays a major role in the proliferation of the gram‐negative bacterium in host organisms. In this work, we test our library of >1000 FKBP‐focused ligands for inhibition of LpMip. The [4.3.1]‐bicyclic sulfonamide turned out as a highly preferred scaffold and provided the most potent LpMip inhibitors known so far. Selected compounds were non‐toxic to human cells, displayed antibacterial activity and block bacterial proliferation in cellular infection‐assays as well as infectivity in human lung tissue explants. The results confirm [4.3.1]‐bicyclic sulfonamides as anti‐legionellal agents, although their anti‐infective properties cannot be explained by inhibition of LpMip alone.

Item Type: Article
Erschienen: 2023
Creators: Deutscher, Robin C. E. ; Safa Karagöz, M. ; Purder, Patrick L. ; Kolos, Jürgen M. ; Meyners, Christian ; Oki Sugiarto, Wisely ; Krajczy, Patryk ; Tebbe, Frederike ; Geiger, Thomas M. ; Ünal, Can ; Hellmich, Ute A. ; Steinert, Michael ; Hausch, Felix
Type of entry: Bibliographie
Title: [4.3.1]Bicyclic FKBP ligands inhibit Legionella Pneumophila infection by LpMip‐dependent and LpMip‐independent mechanisms
Language: English
Date: 2 November 2023
Place of Publication: Weinheim
Publisher: Wiley-VCH
Journal or Publication Title: ChemBioChem
Volume of the journal: 24
Issue Number: 21
Collation: 12 Seiten
DOI: 10.1002/cbic.202300442
Corresponding Links:
Abstract:

Legionella pneumophila is the causative agent of Legionnaires’ disease, a serious form of pneumonia. Its macrophage infectivity potentiator (Mip), a member of a highly conserved family of FK506‐binding proteins (FKBPs), plays a major role in the proliferation of the gram‐negative bacterium in host organisms. In this work, we test our library of >1000 FKBP‐focused ligands for inhibition of LpMip. The [4.3.1]‐bicyclic sulfonamide turned out as a highly preferred scaffold and provided the most potent LpMip inhibitors known so far. Selected compounds were non‐toxic to human cells, displayed antibacterial activity and block bacterial proliferation in cellular infection‐assays as well as infectivity in human lung tissue explants. The results confirm [4.3.1]‐bicyclic sulfonamides as anti‐legionellal agents, although their anti‐infective properties cannot be explained by inhibition of LpMip alone.

Alternative Abstract:
Alternative abstract Language

In a screening of over 1000 FKBP-inhibitors [4.3.1]-bicyclic sulfonamides turned out to be the preferred binding scaffold for LpMip, a virulence factor of Legionella pneumophila. Although selected [4.3.1]-bicyclic sulfonamides showed anti-infective properties, LpMip was ruled out as sole target, with the results suggesting another FKBP is responsible for the observed effects.

English
Uncontrolled Keywords: Antiinfective, Legionella pneumophila, Inhibitors, Isomerases, Medicinal chemistry
Identification Number: Artikel-ID: e202300442
Additional Information:

A previous version of this manuscript has been deposited on a preprint server (https://doi.org/10.26434/chemrxiv-2023-vfssm).

Classification DDC: 500 Science and mathematics > 540 Chemistry
500 Science and mathematics > 570 Life sciences, biology
Divisions: Interdisziplinäre Forschungsprojekte
Interdisziplinäre Forschungsprojekte > Centre for Synthetic Biology
07 Department of Chemistry
07 Department of Chemistry > Clemens-Schöpf-Institut > Fachgebiet Biochemie
07 Department of Chemistry > Clemens-Schöpf-Institut
Date Deposited: 22 May 2024 06:07
Last Modified: 22 May 2024 09:19
PPN: 518469859
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