Lysenko Vladyslav, Son Sangkeun, Theriault Monique E, Slingerland Cornelis J, Hauk Glenn, Cleenewerk Laurence, Speer Alexander, Berger James M, Lewis Kim, Martin Nathaniel I
Biological Chemistry Group, Institute of Biology, Leiden University, Leiden, The Netherlands.
Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA, USA.
Chemistry. 2025 Jan 2;31(1):e202403767. doi: 10.1002/chem.202403767. Epub 2024 Nov 14.
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.
抗生素耐药性带来的威胁不断升级，这是一个全球关注的问题，凸显了新型抗生素的必要性。在此背景下，最近发现的埃维菌素（evybactin）尤其值得关注，它是一种非核糖体缩肽抗生素，能选择性且强效地抑制结核分枝杆菌的生长。在此，我们展示了这种天然产物的首次全合成，并对其指定结构进行了修正。我们的研究揭示了最初提出的埃维菌素结构与其实际构型之间的差异。具体而言，发现埃维菌素核心大环中存在的3-甲基组氨酸残基为d-构型，而非先前指定的l-His(Me)。解决这一问题后，我们进一步优化了固相合成路线，以实现数百毫克规模的埃维菌素制备。获得如此数量的埃维菌素将有助于对这种有前景的抗生素进行更全面的研究。
