Details
| Originalsprache | Englisch |
|---|---|
| Seiten (von - bis) | 567-581 |
| Seitenumfang | 15 |
| Fachzeitschrift | ACS infectious diseases |
| Jahrgang | 9 |
| Ausgabenummer | 3 |
| Frühes Online-Datum | 10 Feb. 2023 |
| Publikationsstatus | Veröffentlicht - 10 März 2023 |
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.
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in: ACS infectious diseases, Jahrgang 9, Nr. 3, 10.03.2023, S. 567-581.
Publikation: Beitrag in Fachzeitschrift › Artikel › Forschung › Peer-Review
}
TY - JOUR
T1 - Molecular Signatures of the Eagle Effect Induced by the Artificial Siderophore Conjugate LP-600 in E. coli
AU - Lai, Yi Hui
AU - Franke, Raimo
AU - Pinkert, Lukas
AU - Overwin, Heike
AU - Brönstrup, Mark
N1 - Funding Information: We thank Ulrike Beutling for technical support with LC-MS measurements, and the sequencing facility of the HZI, led by Dr. Robert Geffers, for the transcriptome analysis.
PY - 2023/3/10
Y1 - 2023/3/10
N2 - 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.
AB - 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.
KW - antibiotics
KW - Eagle effect
KW - Escherichia coli
KW - metabolomics
KW - RNA-sequencing
KW - siderophores
UR - http://www.scopus.com/inward/record.url?scp=85148060785&partnerID=8YFLogxK
U2 - 10.1021/acsinfecdis.2c00567
DO - 10.1021/acsinfecdis.2c00567
M3 - Article
C2 - 36763039
AN - SCOPUS:85148060785
VL - 9
SP - 567
EP - 581
JO - ACS infectious diseases
JF - ACS infectious diseases
SN - 2373-8227
IS - 3
ER -