Full Profiling of GE81112A, an Underexplored Tetrapeptide Antibiotic with Activity against Gram-Negative Pathogens

After the first total synthesis combined with structure revision, we performed thorough and profiling of the underexplored tetrapeptide GE81112A. From the determination of the biological activity spectrum and physicochemical and early absorption-distribution-metabolism-excretion-toxicity (eADMET) pr...

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Published in:	Microbiology spectrum Vol. 11; no. 3; p. e0224722
Main Authors:	Schuler, Sören M M, Jürjens, Gerrit, Marker, Alexander, Hemmann, Ulrike, Rey, Astrid, Yvon, Stéphane, Lagrevol, Marjorie, Hamiti, Mohamed, Nguyen, Fabian, Hirsch, Rolf, Pöverlein, Christoph, Vilcinskas, Andreas, Hammann, Peter, Wilson, Daniel N, Mourez, Michael, Coyne, Sebastien, Bauer, Armin
Format:	Journal Article
Language:	English
Published:	United States American Society for Microbiology 15-06-2023
Subjects:	Animals Anti-Bacterial Agents - chemistry Anti-Bacterial Agents - pharmacology antibiotic Antimicrobial Chemotherapy Drug Resistance, Multiple, Bacterial Escherichia coli Infections - drug therapy GE81112A Gram-Negative Bacteria Humans Mice Microbial Sensitivity Tests profiling Research Article antibiotic profiling GE81112A
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Summary:	After the first total synthesis combined with structure revision, we performed thorough and 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 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. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Present address: Rolf Hirsch, MSD, Frankfurt, Germany. Present address: Sören M. M. Schuler, Evotec International GmbH, Göttingen, Germany. Present address: Astrid Rey, Charles River, Saint-Germain-Nuelles, France. Present address: Sebastien Coyne, Evotec ID (Lyon) SAS, Lyon, France. The authors declare a conflict of interest. A. Marker, U. Hemmann, A. Rey, S. Yvon, M. Lagrevol, M. Hamiti, C. Pöverlein, P. Hammann, M. Mourez, S. Coyne, and A. Bauer are or have been employed by Sanofi or one of its affiliates and are or have been Sanofi shareholders. S. M. M. Schuler, A. Rey, S. Yvon, M. Lagrevol, M. Hamiti, P. Hammann, M. Mourez, and S. Coyne are or have been employed by EVOTEC or one of its affiliates and are or have been EVOTEC shareholders. Present address: Gerrit Jürjens, Helmholtz Zentrum München, Institut für Medizinalchemie, Hannover, Germany. Present address: Marjorie Lagrevol, Evotec ID (Lyon) SAS, Lyon, France. Present address: Fabian Nguyen, Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt, GmbH, Neuherberg, Germany. Present address: Stéphane Yvon, Evotec ID (Lyon) SAS, Lyon, France. Present address: Mohamed Hamiti, Evotec ID (Lyon) SAS, Lyon, France. Present address: Michael Mourez, Purpan Agronomical Engineering School, Toulouse, France. Present address: Daniel N. Wilson, Institut für Biochemie und Molekularbiologie, Universität Hamburg, Hamburg, Germany.
ISSN:	2165-0497 2165-0497
DOI:	10.1128/spectrum.02247-22