Details
| Original language | English |
|---|---|
| Pages (from-to) | 8981-8990 |
| Number of pages | 10 |
| Journal | Journal of the American Chemical Society |
| Volume | 146 |
| Issue number | 13 |
| Early online date | 21 Mar 2024 |
| Publication status | Published - 3 Apr 2024 |
Abstract
The rapid development of antibiotic resistance, especially among difficult-to-treat Gram-negative bacteria, is recognized as a serious and urgent threat to public health. The detection and characterization of novel resistance mechanisms are essential to better predict the spread and evolution of antibiotic resistance. Corramycin is a novel and modified peptidic antibiotic with activity against several Gram-negative pathogens. We demonstrate that the kinase ComG, part of the corramycin biosynthetic gene cluster, phosphorylates and thereby inactivates corramycin, leading to the resistance of the host. Remarkably, we found that the closest structural homologues of ComG are aminoglycoside phosphotransferases; however, ComG shows no activity toward this class of antibiotics. The crystal structure of ComG in complex with corramycin reveals that corramycin adopts a β-hairpin-like structure and allowed us to define the changes leading to a switch in substrate from sugar to peptide. Bioinformatic analyses suggest a limited occurrence of ComG-like proteins, which along with the absence of cross-resistance to clinically used drugs positions corramycin as an attractive antibiotic for further development.
ASJC Scopus subject areas
- Chemical Engineering(all)
- Catalysis
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Biochemistry
- Chemical Engineering(all)
- Colloid and Surface Chemistry
Sustainable Development Goals
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In: Journal of the American Chemical Society, Vol. 146, No. 13, 03.04.2024, p. 8981-8990.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - The Peptide Antibiotic Corramycin Adopts a β-Hairpin-like Structure and Is Inactivated by the Kinase ComG
AU - Adam, Sebastian
AU - Fries, Franziska
AU - von Tesmar, Alexander
AU - Rasheed, Sari
AU - Deckarm, Selina
AU - Sousa, Carla F.
AU - Reberšek, Roman
AU - Risch, Timo
AU - Mancini, Stefano
AU - Herrmann, Jennifer
AU - Koehnke, Jesko
AU - Kalinina, Olga V.
AU - Müller, Rolf
N1 - Funding Information: This study was supported by the German Centre for Infection Research (DZIF) in the project “Development of corramycin as an antibiotic against Gram-negative bacteria” (project: TTU 09.827, funding code: 8004809827) and the European Research Council (ERC CoG 101002326) (to J.K.).
PY - 2024/4/3
Y1 - 2024/4/3
N2 - The rapid development of antibiotic resistance, especially among difficult-to-treat Gram-negative bacteria, is recognized as a serious and urgent threat to public health. The detection and characterization of novel resistance mechanisms are essential to better predict the spread and evolution of antibiotic resistance. Corramycin is a novel and modified peptidic antibiotic with activity against several Gram-negative pathogens. We demonstrate that the kinase ComG, part of the corramycin biosynthetic gene cluster, phosphorylates and thereby inactivates corramycin, leading to the resistance of the host. Remarkably, we found that the closest structural homologues of ComG are aminoglycoside phosphotransferases; however, ComG shows no activity toward this class of antibiotics. The crystal structure of ComG in complex with corramycin reveals that corramycin adopts a β-hairpin-like structure and allowed us to define the changes leading to a switch in substrate from sugar to peptide. Bioinformatic analyses suggest a limited occurrence of ComG-like proteins, which along with the absence of cross-resistance to clinically used drugs positions corramycin as an attractive antibiotic for further development.
AB - The rapid development of antibiotic resistance, especially among difficult-to-treat Gram-negative bacteria, is recognized as a serious and urgent threat to public health. The detection and characterization of novel resistance mechanisms are essential to better predict the spread and evolution of antibiotic resistance. Corramycin is a novel and modified peptidic antibiotic with activity against several Gram-negative pathogens. We demonstrate that the kinase ComG, part of the corramycin biosynthetic gene cluster, phosphorylates and thereby inactivates corramycin, leading to the resistance of the host. Remarkably, we found that the closest structural homologues of ComG are aminoglycoside phosphotransferases; however, ComG shows no activity toward this class of antibiotics. The crystal structure of ComG in complex with corramycin reveals that corramycin adopts a β-hairpin-like structure and allowed us to define the changes leading to a switch in substrate from sugar to peptide. Bioinformatic analyses suggest a limited occurrence of ComG-like proteins, which along with the absence of cross-resistance to clinically used drugs positions corramycin as an attractive antibiotic for further development.
UR - http://www.scopus.com/inward/record.url?scp=85188420194&partnerID=8YFLogxK
U2 - 10.1021/jacs.3c13208
DO - 10.1021/jacs.3c13208
M3 - Article
C2 - 38513269
AN - SCOPUS:85188420194
VL - 146
SP - 8981
EP - 8990
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
SN - 0002-7863
IS - 13
ER -