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

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, Michaël; Coyne, S J; Bauer, Armin

doi:10.1128/spectrum.02247-22

Microbiol Spectr

2023

DOI: 10.1128/spectrum.02247-22

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

Sören M. M. Schuler

Gerrit Jürjens

Alexander Marker

et al.

Abstract: 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.

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Cited by 2 publications

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Natural Products That Contain Higher Homologated Amino Acids

Owens,

Ahmed,

Lang Harman

et al. 2024

ChemBioChem

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This review focuses on discussing natural products (NPs) that contain higher homologs of amino acids (homoAAs) in the structure as well as the proposed and characterized biosynthesis of these non‐proteinogenic amino acids. Homologation of amino acids includes the insertion of a methylene group into its side chain. It is not a very common modification found in NP biosynthesis as approximately 450 homoAA‐containing NPs have been isolated from four bacterial phyla (Cyanobacteria, Actinomycetota, Myxococcota, and Pseudomonadota), two fungal phyla (Ascomycota and Basidiomycota), and one animal phylum (Porifera), except for a few examples. Amino acids that are found to be homologated and incorporated in the NP structures include the following ten amino acids: alanine, arginine, cysteine, isoleucine, glutamic acid, leucine, phenylalanine, proline, serine, and tyrosine, where isoleucine, leucine, phenylalanine, and tyrosine share the comparable enzymatic pathway. Other amino acids have their individual homologation pathway (arginine, proline, and glutamic acid for bacteria), likely utilize the primary metabolic pathway (alanine and glutamic acid for fungi), or have not been reported (cysteine and serine). Despite its possible high potential in the drug discovery field, the biosynthesis of homologated amino acids has a large room to explore for future combinatorial biosynthesis and metabolic engineering purpose.

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Natural Products That Contain Higher Homologated Amino Acids

Owens,

Ahmed,

Lang Harman

et al. 2024

ChemBioChem

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Total Synthesis of GE81112A: An Orthoester-Based Approach

et al. 2023

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The GE81112 series, consisting of three naturally occurring tetrapeptides and synthetic derivatives, is evaluated as a potential lead structure for the development of a new antibacterial drug. Although the first total synthesis of GE81112A reported by our group provided sufficient amounts of material for an initial in depth biological profiling of the compound, improvements of the routes toward the key building blocks were needed for further upscaling and structure–activity relationship studies. The major challenges identified were poor stereoselectivity in the synthesis of the C-terminal β-hydroxy histidine intermediate and a concise access to all four isomers of the 3-hydroxy pipecolic acid. Herein, we report a second-generation synthesis of GE81112A, which is also applicable to access further representatives of this series. Based on Lajoie’s ortho-ester-protected serine aldehydes as key building blocks, the described route provides both a satisfactory improvement in stereoselectivity of the β-hydroxy histidine intermediate synthesis and a stereoselective approach toward both orthogonally protected cis and trans-3-hydroxy pipecolic acid.

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

Abstract: 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.

Cited by 2 publications

References 17 publications

Natural Products That Contain Higher Homologated Amino Acids

Natural Products That Contain Higher Homologated Amino Acids

Total Synthesis of GE81112A: An Orthoester-Based Approach

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