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 -