TY - JOUR

T1 - Synthesis and Characterization of DOTAM-Based Sideromycins for Bacterial Imaging and Antimicrobial Therapy

AU - Peukert, Carsten

AU - Rox, Katharina

AU - Karge, Bianka

AU - Hotop, Sven Kevin

AU - Brönstrup, Mark

N1 - Funding Information: We acknowledge the funding by the Joint Program Initiative on Antimicrobial Resistance (JPI AMR, grant number: 01KI1825). C.P. thanks the “Fonds der chemischen Industrie” for a scholarship. K.R. and M.B. received support from the German Centre for Infection Research (DZIF, TTU 09.719 and TTU 09.722). We further acknowledge the support from the Helmholtz International Lab for anti-infectives. Funding Information: We thank Kirsten Harmrolfs and Christel Kakoschke for the measurement of NMR samples, Andrea Ahlers and Jennifer Wolf for technical assistance, and Ulrike Beutling for the mass spectrometric measurements. We are thankful to Marc Stadler and the Department of Microbial Drugs (MWIS) at the Helmholtz Centre for Infection Research for providing us sorangicin A.

PY - 2023/1/31

Y1 - 2023/1/31

N2 - 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.

AB - 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.

KW - antibiotic conjugates

KW - diagnostics

KW - drug delivery

KW - siderophores

KW - theranostic

KW - Trojan horse

UR - http://www.scopus.com/inward/record.url?scp=85147834462&partnerID=8YFLogxK

U2 - 10.1021/acsinfecdis.2c00523

DO - 10.1021/acsinfecdis.2c00523

M3 - Article

C2 - 36719860

AN - SCOPUS:85147834462

VL - 9

SP - 330

EP - 341

JO - ACS infectious diseases

JF - ACS infectious diseases

SN - 2373-8227

IS - 2

ER -