[4.3.1]Bicyclic FKBP Ligands Inhibit Legionella Pneumophila Infection by LpMip‐Dependent and LpMip‐Independent Mechanisms

Deutscher, Robin C. E. ; Karagöz, Mustafa Safa ; 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 (2024)
[4.3.1]Bicyclic FKBP Ligands Inhibit Legionella Pneumophila Infection by LpMip‐Dependent and LpMip‐Independent Mechanisms.
In: ChemBioChem, 2023, 24 (21)
doi: 10.26083/tuprints-00027244
Article, Secondary publication, Publisher's Version

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Item Type:

Article

Type of entry:

Secondary publication

Title:

[4.3.1]Bicyclic FKBP Ligands Inhibit Legionella Pneumophila Infection by LpMip‐Dependent and LpMip‐Independent Mechanisms

Language:

English

Date:

21 May 2024

Place of Publication:

Darmstadt

Year of primary publication:

2 November 2023

Place of primary publication:

Weinheim

Publisher:

Wiley-VCH

Journal or Publication Title:

ChemBioChem

Volume of the journal:

Issue Number:

Collation:

12 Seiten

DOI:

10.26083/tuprints-00027244

Corresponding Links:

Origin:

Secondary publication DeepGreen

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

Status:

Publisher's Version

URN:

urn:nbn:de:tuda-tuprints-272444

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