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

Publikation: Beitrag in FachzeitschriftArtikelForschungPeer-Review

Autoren

  • Sören M.M. Schuler
  • Gerrit Jürjens
  • Alexander Marker
  • Ulrike Hemmann
  • Astrid Rey
  • Stéphane Yvon
  • Marjorie Lagrevol
  • Mohamed Hamiti
  • Fabian Nguyen
  • Rolf Hirsch
  • Christoph Pöverlein
  • Andreas Vilcinskas
  • Peter Hammann
  • Daniel N. Wilson
  • Michael Mourez
  • Sebastien Coyne
  • Armin Bauer

Externe Organisationen

  • Fraunhofer-Institut Molekularbiologie und Angewandte Oekologie IME
  • Sanofi-Aventis Deutschland GmbH
  • Sanofi-Aventis France
  • Ludwig-Maximilians-Universität München (LMU)
  • Justus-Liebig-Universität Gießen
Forschungs-netzwerk anzeigen

Details

OriginalspracheEnglisch
FachzeitschriftMicrobiology spectrum
Jahrgang11
Ausgabenummer3
Frühes Online-Datum4 Mai 2023
PublikationsstatusElektronisch veröffentlicht (E-Pub) - 4 Mai 2023
Extern publiziertJa

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.

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Full Profiling of GE81112A, an Underexplored Tetrapeptide Antibiotic with Activity against Gram-Negative Pathogens. / Schuler, Sören M.M.; Jürjens, Gerrit; Marker, Alexander et al.
in: Microbiology spectrum, Jahrgang 11, Nr. 3, 04.05.2023.

Publikation: Beitrag in FachzeitschriftArtikelForschungPeer-Review

Schuler, SMM, Jürjens, G, Marker, A, Hemmann, U, Rey, A, Yvon, S, Lagrevol, M, Hamiti, M, Nguyen, F, Hirsch, R, Pöverlein, C, Vilcinskas, A, Hammann, P, Wilson, DN, Mourez, M, Coyne, S & Bauer, A 2023, 'Full Profiling of GE81112A, an Underexplored Tetrapeptide Antibiotic with Activity against Gram-Negative Pathogens', Microbiology spectrum, Jg. 11, Nr. 3. https://doi.org/10.1128/spectrum.02247-22
Schuler, S. M. M., Jürjens, G., Marker, A., Hemmann, U., Rey, A., Yvon, S., Lagrevol, M., Hamiti, M., Nguyen, F., Hirsch, R., Pöverlein, C., Vilcinskas, A., Hammann, P., Wilson, D. N., Mourez, M., Coyne, S., & Bauer, A. (2023). Full Profiling of GE81112A, an Underexplored Tetrapeptide Antibiotic with Activity against Gram-Negative Pathogens. Microbiology spectrum, 11(3). Vorabveröffentlichung online. https://doi.org/10.1128/spectrum.02247-22
Schuler SMM, Jürjens G, Marker A, Hemmann U, Rey A, Yvon S et al. Full Profiling of GE81112A, an Underexplored Tetrapeptide Antibiotic with Activity against Gram-Negative Pathogens. Microbiology spectrum. 2023 Mai 4;11(3). Epub 2023 Mai 4. doi: 10.1128/spectrum.02247-22
Schuler, Sören M.M. ; Jürjens, Gerrit ; Marker, Alexander et al. / Full Profiling of GE81112A, an Underexplored Tetrapeptide Antibiotic with Activity against Gram-Negative Pathogens. in: Microbiology spectrum. 2023 ; Jahrgang 11, Nr. 3.
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title = "Full Profiling of GE81112A, an Underexplored Tetrapeptide Antibiotic with Activity against Gram-Negative Pathogens",
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.",
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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

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Y1 - 2023/5/4

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