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

authored by

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.

Organisation(s)

Institute of Organic Chemistry

External Organisation(s)

Helmholtz Centre for Infection Research (HZI)
German Center for Infection Research (DZIF)

Type

Article

Journal

ACS infectious diseases

Volume

9

Pages

330-341

No. of pages

12

ISSN

2373-8227

Publication date

31.01.2023

Publication status

Published

Peer reviewed

Yes

ASJC Scopus subject areas

Infectious Diseases

Sustainable Development Goals

SDG 3 - Good Health and Well-being

Electronic version(s)

https://doi.org/10.1021/acsinfecdis.2c00523 (Access: Open)