Details
| Original language | English |
|---|---|
| Journal | Microbiology spectrum |
| Volume | 11 |
| Issue number | 3 |
| Early online date | 4 May 2023 |
| Publication status | E-pub ahead of print - 4 May 2023 |
| Externally published | Yes |
Abstract
After the first total synthesis combined with structure revision, we performed thorough in vitro and in vivo profiling of the underexplored tetrapeptide GE81112A. From the determination of the biological activity spectrum and physicochemical and early absorption-distribution-metabolism-excretion-toxicity (eADMET) properties, as well as in vivo data regarding tolerability and pharmacokinetics (PK) in mice and efficacy in an Escherichia coli-induced septicemia model, we were able to identify the critical and limiting parameters of the original hit compound. Thus, the generated data will serve as the basis for further compound optimization programs and developability assessments to identify candidates for preclinical/clinical development derived from GE81112A as the lead structure. IMPORTANCE The spread of antimicrobial resistance (AMR) is becoming a more and more important global threat to human health. With regard to current medical needs, penetration into the site of infection represents the major challenge in the treatment of infections caused by Gram-positive bacteria. Considering infections associated with Gram-negative bacteria, resistance is a major issue. Obviously, novel scaffolds for the design of new antibacterials in this arena are urgently needed to overcome this crisis. Such a novel potential lead structure is represented by the GE81112 compounds, which inhibit protein synthesis by interacting with the small 30S ribosomal subunit using a binding site distinct from that of other known ribosome-targeting antibiotics. Therefore, the tetrapeptide antibiotic GE81112A was chosen for further exploration as a potential lead for the development of antibiotics with a new mode of action against Gram-negative bacteria.
Keywords
- antibiotic, GE81112A, profiling
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Physiology
- Environmental Science(all)
- Ecology
- Immunology and Microbiology(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Genetics
- Medicine(all)
- Microbiology (medical)
- Biochemistry, Genetics and Molecular Biology(all)
- Cell Biology
- Medicine(all)
- Infectious Diseases
Sustainable Development Goals
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In: Microbiology spectrum, Vol. 11, No. 3, 04.05.2023.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Full Profiling of GE81112A, an Underexplored Tetrapeptide Antibiotic with Activity against Gram-Negative Pathogens
AU - Schuler, Sören M.M.
AU - Jürjens, Gerrit
AU - Marker, Alexander
AU - Hemmann, Ulrike
AU - Rey, Astrid
AU - Yvon, Stéphane
AU - Lagrevol, Marjorie
AU - Hamiti, Mohamed
AU - Nguyen, Fabian
AU - Hirsch, Rolf
AU - Pöverlein, Christoph
AU - Vilcinskas, Andreas
AU - Hammann, Peter
AU - Wilson, Daniel N.
AU - Mourez, Michael
AU - Coyne, Sebastien
AU - Bauer, Armin
N1 - Funding Information: This work was supported by the Hesse State Ministry of Higher Education, Research, and the Arts (HMWK) via a generous grant for the LOEWE Center for Insect Biotechnology and Bioresources. Sanofi and Evotec International contributed in the framework of the Sanofi-Fraunhofer Natural Product Center of Excellence/Fraunhofer Evotec Natural Products Excellence Center. Antibiotic research in the Wilson group is funded by Deutsche Forschungsgemeinschaft (grant WI3285/6-1) and the Deutsche Zentrum für Luft- und Raumfahrt (grant DLR01Kl1820) within the RIBOTARGET consortium under the frame of the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR).
PY - 2023/5/4
Y1 - 2023/5/4
N2 - After the first total synthesis combined with structure revision, we performed thorough in vitro and in vivo profiling of the underexplored tetrapeptide GE81112A. From the determination of the biological activity spectrum and physicochemical and early absorption-distribution-metabolism-excretion-toxicity (eADMET) properties, as well as in vivo data regarding tolerability and pharmacokinetics (PK) in mice and efficacy in an Escherichia coli-induced septicemia model, we were able to identify the critical and limiting parameters of the original hit compound. Thus, the generated data will serve as the basis for further compound optimization programs and developability assessments to identify candidates for preclinical/clinical development derived from GE81112A as the lead structure. IMPORTANCE The spread of antimicrobial resistance (AMR) is becoming a more and more important global threat to human health. With regard to current medical needs, penetration into the site of infection represents the major challenge in the treatment of infections caused by Gram-positive bacteria. Considering infections associated with Gram-negative bacteria, resistance is a major issue. Obviously, novel scaffolds for the design of new antibacterials in this arena are urgently needed to overcome this crisis. Such a novel potential lead structure is represented by the GE81112 compounds, which inhibit protein synthesis by interacting with the small 30S ribosomal subunit using a binding site distinct from that of other known ribosome-targeting antibiotics. Therefore, the tetrapeptide antibiotic GE81112A was chosen for further exploration as a potential lead for the development of antibiotics with a new mode of action against Gram-negative bacteria.
AB - After the first total synthesis combined with structure revision, we performed thorough in vitro and in vivo profiling of the underexplored tetrapeptide GE81112A. From the determination of the biological activity spectrum and physicochemical and early absorption-distribution-metabolism-excretion-toxicity (eADMET) properties, as well as in vivo data regarding tolerability and pharmacokinetics (PK) in mice and efficacy in an Escherichia coli-induced septicemia model, we were able to identify the critical and limiting parameters of the original hit compound. Thus, the generated data will serve as the basis for further compound optimization programs and developability assessments to identify candidates for preclinical/clinical development derived from GE81112A as the lead structure. IMPORTANCE The spread of antimicrobial resistance (AMR) is becoming a more and more important global threat to human health. With regard to current medical needs, penetration into the site of infection represents the major challenge in the treatment of infections caused by Gram-positive bacteria. Considering infections associated with Gram-negative bacteria, resistance is a major issue. Obviously, novel scaffolds for the design of new antibacterials in this arena are urgently needed to overcome this crisis. Such a novel potential lead structure is represented by the GE81112 compounds, which inhibit protein synthesis by interacting with the small 30S ribosomal subunit using a binding site distinct from that of other known ribosome-targeting antibiotics. Therefore, the tetrapeptide antibiotic GE81112A was chosen for further exploration as a potential lead for the development of antibiotics with a new mode of action against Gram-negative bacteria.
KW - antibiotic
KW - GE81112A
KW - profiling
UR - http://www.scopus.com/inward/record.url?scp=85152138947&partnerID=8YFLogxK
U2 - 10.1128/spectrum.02247-22
DO - 10.1128/spectrum.02247-22
M3 - Article
C2 - 37140391
AN - SCOPUS:85152138947
VL - 11
JO - Microbiology spectrum
JF - Microbiology spectrum
SN - 2165-0497
IS - 3
ER -