Details
| Original language | English |
|---|---|
| Article number | 252 |
| Journal | Communications Chemistry |
| Volume | 7 |
| Issue number | 1 |
| Publication status | Published - 5 Nov 2024 |
Abstract
Novel scaffolds for broad-spectrum antibiotics are rare and in strong demand because of the increase in antimicrobial resistance. The cystobactamids, discovered from myxobacterial sources, have a unique hexapeptidic scaffold with five arylamides and possess potent, resistance-breaking properties. This study investigates the role of the central D-ring pharmacophore in cystobactamids, a para-aminobenzoic acid (PABA) moiety that is additionally substituted by hydroxy and isopropoxy functions. We varied the two oxygenated substituents and replaced both amide connectors with bioisosteres. Synthetic routes were developed that included metal-mediated aromatic functionalization or heterocycle formations, leading to 19 novel analogues. The antibiotic efficacy of all analogues was determined against bacteria from the ESKAPE pathogen panel. While the replacement and the repositioning of hydroxy and isopropoxy substituents was not advantageous, exchanging PABA by terephthalic acid amides led to the highly potent analogue 42 with broad-spectrum activity, insensitivity towards AlbD-mediated degradation and promising pharmacokinetic properties in mice. The study highlights the steep structure-activity relationships in the tetrasubstituted D-ring and a surprisingly favorable reversion of the amide connecting C and D.
ASJC Scopus subject areas
- Chemistry(all)
- Environmental Science(all)
- Environmental Chemistry
- Biochemistry, Genetics and Molecular Biology(all)
- Biochemistry
- Materials Science(all)
- Materials Chemistry
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In: Communications Chemistry, Vol. 7, No. 1, 252, 05.11.2024.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Synthetic studies on the tetrasubstituted D-ring of cystobactamids lead to potent terephthalic acid antibiotics
AU - Stappert, Moritz
AU - Kohnhäuser, Daniel
AU - Seedorf, Tim
AU - Coetzee, Janetta
AU - Rox, Katharina
AU - Fuchs, Hazel L.S.
AU - Cirnski, Katarina
AU - Leitner, Christian
AU - Herrmann, Jennifer
AU - Kirschning, Andreas
AU - Müller, Rolf
AU - Brönstrup, Mark
N1 - Publisher Copyright: © The Author(s) 2024.
PY - 2024/11/5
Y1 - 2024/11/5
N2 - Novel scaffolds for broad-spectrum antibiotics are rare and in strong demand because of the increase in antimicrobial resistance. The cystobactamids, discovered from myxobacterial sources, have a unique hexapeptidic scaffold with five arylamides and possess potent, resistance-breaking properties. This study investigates the role of the central D-ring pharmacophore in cystobactamids, a para-aminobenzoic acid (PABA) moiety that is additionally substituted by hydroxy and isopropoxy functions. We varied the two oxygenated substituents and replaced both amide connectors with bioisosteres. Synthetic routes were developed that included metal-mediated aromatic functionalization or heterocycle formations, leading to 19 novel analogues. The antibiotic efficacy of all analogues was determined against bacteria from the ESKAPE pathogen panel. While the replacement and the repositioning of hydroxy and isopropoxy substituents was not advantageous, exchanging PABA by terephthalic acid amides led to the highly potent analogue 42 with broad-spectrum activity, insensitivity towards AlbD-mediated degradation and promising pharmacokinetic properties in mice. The study highlights the steep structure-activity relationships in the tetrasubstituted D-ring and a surprisingly favorable reversion of the amide connecting C and D.
AB - Novel scaffolds for broad-spectrum antibiotics are rare and in strong demand because of the increase in antimicrobial resistance. The cystobactamids, discovered from myxobacterial sources, have a unique hexapeptidic scaffold with five arylamides and possess potent, resistance-breaking properties. This study investigates the role of the central D-ring pharmacophore in cystobactamids, a para-aminobenzoic acid (PABA) moiety that is additionally substituted by hydroxy and isopropoxy functions. We varied the two oxygenated substituents and replaced both amide connectors with bioisosteres. Synthetic routes were developed that included metal-mediated aromatic functionalization or heterocycle formations, leading to 19 novel analogues. The antibiotic efficacy of all analogues was determined against bacteria from the ESKAPE pathogen panel. While the replacement and the repositioning of hydroxy and isopropoxy substituents was not advantageous, exchanging PABA by terephthalic acid amides led to the highly potent analogue 42 with broad-spectrum activity, insensitivity towards AlbD-mediated degradation and promising pharmacokinetic properties in mice. The study highlights the steep structure-activity relationships in the tetrasubstituted D-ring and a surprisingly favorable reversion of the amide connecting C and D.
UR - http://www.scopus.com/inward/record.url?scp=85208707095&partnerID=8YFLogxK
U2 - 10.1038/s42004-024-01337-6
DO - 10.1038/s42004-024-01337-6
M3 - Article
AN - SCOPUS:85208707095
VL - 7
JO - Communications Chemistry
JF - Communications Chemistry
IS - 1
M1 - 252
ER -