Total Synthesis and Structural Reassignment of the Antitubercular Natural Product Evybactin

The escalating threat posed by antibiotic resistance is a global concern and underscores the need for new antibiotics. In this context, the recent discovery of evybactin, a nonribosomal depsipeptide antibiotic that selectively and potently inhibits the growth of M. tuberculosis, is particularly noteworthy. Here, we present the first total synthesis of this natural product, along with a revision of its assigned structure. Our studies revealed a disparity between the structure originally proposed for evybactin and its actual configuration. Specifically, the 3-methylhistidine residue present in the evybactin core macrocycle was found to be of the d-configuration rather than the previously assigned l-His(Me). Having addressed this, we further optimized our solid-phase synthetic route to provide access to evybactin on a multi-hundred-milligram scale. Access to such quantities will allow for more comprehensive studies with this promising antibiotic.

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Publication Details

Journal
Chemistry - A European Journal
Published
2024-10-16
DOI
https://doi.org/10.1002/chem.202403767
Citations
4
Primary Topic
Microbial Natural Products and Biosynthesis
Type
article
Field-Weighted Citation Impact
1.79

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article

Total Synthesis and Structural Reassignment of the Antitubercular Natural Product Evybactin

Sangkeun Son, Glenn Hauk, James M. Berger, Laurence Cleenewerk et al.
4 citations
Chemistry - A European Journal
Microbial Natural Products and Biosynthesis
1.79
article

Total Synthesis and Structural Reassignment of the Antitubercular Natural Product Evybactin

Sangkeun Son, Glenn Hauk, James M. Berger, Laurence Cleenewerk, Alexander Speer, Cornelis J. Slingerland, Nathaniel I. Martin, Kim Lewis, Vladyslav Lysenko, Monique E. Theriault
article en
4 citations

Abstract

The escalating threat posed by antibiotic resistance is a global concern and underscores the need for new antibiotics. In this context, the recent discovery of evybactin, a nonribosomal depsipeptide antibiotic that selectively and potently inhibits the growth of M. tuberculosis, is particularly noteworthy. Here, we present the first total synthesis of this natural product, along with a revision of its assigned structure. Our studies revealed a disparity between the structure originally proposed for evybactin and its actual configuration. Specifically, the 3-methylhistidine residue present in the evybactin core macrocycle was found to be of the d-configuration rather than the previously assigned l-His(Me). Having addressed this, we further optimized our solid-phase synthetic route to provide access to evybactin on a multi-hundred-milligram scale. Access to such quantities will allow for more comprehensive studies with this promising antibiotic.

Chemistry - A European JournalVol. 31(1)
Leiden University (NL), Northeastern University (US), Johns Hopkins University (US), University of Applied Sciences Leiden (NL), Johns Hopkins Medicine (US), Vrije Universiteit Amsterdam (NL), Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
Foundation for the National Institutes of Health, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, National Institutes of Health
Openalex Percentile: Top 15%
Microbial Natural Products and Biosynthesis
1.79
DOIOpen Access PDFOpenAlex
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