Molecular Signatures of the Eagle Effect Induced by the Artificial Siderophore Conjugate LP-600 in E. coli

verfasst von

Yi Hui Lai, Raimo Franke, Lukas Pinkert, Heike Overwin, Mark Brönstrup

Abstract

Achieving cellular uptake is a central challenge for novel antibiotics targeting Gram-negative bacterial pathogens. One strategy is to hijack the bacterial iron transport system by siderophore-antibiotic conjugates that are actively imported into the cell. This was realized with the MECAM-ampicillin conjugate LP-600 we recently reported that was highly active against E. coli. In the present study, we investigate a paradoxical regrowth of E. coli upon treatment of LP-600 at concentrations 16-32 times above the minimum inhibitory concentration (MIC). The phenomenon, coined “Eagle-effect” in other systems, was not due to resistance formation, and it occurred for the siderophore conjugate but not for free ampicillin. To investigate the molecular imprint of the Eagle effect, a combined transcriptome and untargeted metabolome analysis was conducted. LP-600 induced the expression of genes involved in iron acquisition, SOS response, and the e14 prophage upon regrowth conditions. The Eagle effect was diminished in the presence of sulbactam, which we ascribe to a putative synergistic antibiotic action but not to β-lactamase inhibition. The study highlights the relevance of the Eagle effect for siderophore conjugates. Through the first systematic -omics investigations, it also demonstrates that the Eagle effect manifests not only in a paradoxical growth but also in unique gene expression and metabolite profiles.

Organisationseinheit(en)

Zentrum für Biomolekulare Wirkstoffe (BMWZ)

Externe Organisation(en)

Helmholtz-Zentrum für Infektionsforschung GmbH (HZI)
Deutsches Zentrum für Infektionsforschung (DZIF)

Typ

Artikel

Journal

ACS infectious diseases

Band

9

Seiten

567-581

Anzahl der Seiten

15

ISSN

2373-8227

Publikationsdatum

10.03.2023

Publikationsstatus

Veröffentlicht

Peer-reviewed

Ja

ASJC Scopus Sachgebiete

Infektionskrankheiten

Ziele für nachhaltige Entwicklung

SDG 3 – Gute Gesundheit und Wohlergehen

Elektronische Version(en)

https://doi.org/10.1021/acsinfecdis.2c00567 (Zugang: Offen)