Synthesis and Characterization of DOTAM-Based Sideromycins for Bacterial Imaging and Antimicrobial Therapy

verfasst von

Carsten Peukert, Katharina Rox, Bianka Karge, Sven Kevin Hotop, Mark Brönstrup

Abstract

The rise of antimicrobial resistance, especially in Gram-negative bacteria, calls for novel diagnostics and antibiotics. To efficiently penetrate their double-layered cell membrane, we conjugated the potent antibiotics daptomycin, vancomycin, and sorangicin A to catechol siderophores, which are actively internalized by the bacterial iron uptake machinery. LC-MS/MS uptake measurements of sorangicin derivatives verified that the conjugation led to a 100- to 525-fold enhanced uptake into bacteria compared to the free drug. However, the transfer to the cytosol was insufficient, which explains their lack of antibiotic efficacy. Potent antimicrobial effects were observed for the daptomycin conjugate 7 (∼1 μM) against multidrug-resistant Acinetobacter baumannii. A cyanin-7 label aside the daptomycin warhead furnished the theranostic 13 that retained its antibiotic activity and was also able to label ESKAPE bacteria, as demonstrated by microscopy and fluorescence assays. 13 and the cyanin-7 imaging conjugate 14 were stable in human plasma and had low plasma protein binding and cytotoxicity.

Organisationseinheit(en)

Institut für Organische Chemie

Externe Organisation(en)

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

Typ

Artikel

Journal

ACS infectious diseases

Band

9

Seiten

330-341

Anzahl der Seiten

12

ISSN

2373-8227

Publikationsdatum

31.01.2023

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.2c00523 (Zugang: Offen)