Details
| Original language | English |
|---|---|
| Pages (from-to) | 15440–15460 |
| Number of pages | 21 |
| Journal | Journal of medicinal chemistry |
| Volume | 64 |
| Issue number | 20 |
| Early online date | 8 Oct 2021 |
| Publication status | Published - 28 Oct 2021 |
Abstract
The development of novel drugs against Gram-negative bacteria represents an urgent medical need. To overcome their outer cell membrane, we synthesized conjugates of antibiotics and artificial siderophores based on the MECAM core, which are imported by bacterial iron uptake systems. Structures, spin states, and iron binding properties were predicted in silico using density functional theory. The capability of MECAM to function as an effective artificial siderophore in Escherichia coli was proven in microbiological growth recovery and bioanalytical assays. Following a linker optimization focused on transport efficiency, five β-lactam and one daptomycin conjugates were prepared. The most potent conjugate 27 showed growth inhibition of Gram-positive and Gram-negative multidrug-resistant pathogens at nanomolar concentrations. The uptake pathway of MECAMs was deciphered by knockout mutants and highlighted the relevance of FepA, CirA, and Fiu. Resistance against 27 was mediated by a mutation in the gene encoding ExbB, which is involved in siderophore transport.
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Molecular Medicine
- Pharmacology, Toxicology and Pharmaceutics(all)
- Drug Discovery
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In: Journal of medicinal chemistry, Vol. 64, No. 20, 28.10.2021, p. 15440–15460.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Antibiotic Conjugates with an Artificial MECAM-Based Siderophore Are Potent Agents against Gram-Positive and Gram-Negative Bacterial Pathogens
AU - Pinkert, Lukas
AU - Lai, Yi Hui
AU - Peukert, Carsten
AU - Hotop, Sven Kevin
AU - Karge, Bianka
AU - Schulze, Lara Marie
AU - Grunenberg, Jörg
AU - Brönstrup, Mark
N1 - Funding Information: This project was funded by the DFG (grant number: BR 3572/4-1) and the Joint Program Initiative on Antimicrobial Resistance (JPI AMR, grant number: 01KI1825). C.P. thanks the “Fonds der chemischen Industrie” for a scholarship.
PY - 2021/10/28
Y1 - 2021/10/28
N2 - The development of novel drugs against Gram-negative bacteria represents an urgent medical need. To overcome their outer cell membrane, we synthesized conjugates of antibiotics and artificial siderophores based on the MECAM core, which are imported by bacterial iron uptake systems. Structures, spin states, and iron binding properties were predicted in silico using density functional theory. The capability of MECAM to function as an effective artificial siderophore in Escherichia coli was proven in microbiological growth recovery and bioanalytical assays. Following a linker optimization focused on transport efficiency, five β-lactam and one daptomycin conjugates were prepared. The most potent conjugate 27 showed growth inhibition of Gram-positive and Gram-negative multidrug-resistant pathogens at nanomolar concentrations. The uptake pathway of MECAMs was deciphered by knockout mutants and highlighted the relevance of FepA, CirA, and Fiu. Resistance against 27 was mediated by a mutation in the gene encoding ExbB, which is involved in siderophore transport.
AB - The development of novel drugs against Gram-negative bacteria represents an urgent medical need. To overcome their outer cell membrane, we synthesized conjugates of antibiotics and artificial siderophores based on the MECAM core, which are imported by bacterial iron uptake systems. Structures, spin states, and iron binding properties were predicted in silico using density functional theory. The capability of MECAM to function as an effective artificial siderophore in Escherichia coli was proven in microbiological growth recovery and bioanalytical assays. Following a linker optimization focused on transport efficiency, five β-lactam and one daptomycin conjugates were prepared. The most potent conjugate 27 showed growth inhibition of Gram-positive and Gram-negative multidrug-resistant pathogens at nanomolar concentrations. The uptake pathway of MECAMs was deciphered by knockout mutants and highlighted the relevance of FepA, CirA, and Fiu. Resistance against 27 was mediated by a mutation in the gene encoding ExbB, which is involved in siderophore transport.
UR - http://www.scopus.com/inward/record.url?scp=85117450279&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.1c01482
DO - 10.1021/acs.jmedchem.1c01482
M3 - Article
AN - SCOPUS:85117450279
VL - 64
SP - 15440
EP - 15460
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
SN - 0022-2623
IS - 20
ER -