Amythiamicin D and Related Thiopeptides as Inhibitors of the Bacterial Elongation Factor EF-Tu: Modification of the Amino Acid at Carbon Atom C2 of Ring C Dramatically Influences Activity

Authors / Editors

Gross, Said

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Publication Details

Output type: Journal article

Author list: Gross S, Nguyen F, Bierschenk M, Sohmen D, Menzel T, Antes I, Wilson DN, Bach T

Publisher: Wiley

Publication year: 2013

Journal: ChemMedChem (1860-7179)

Volume number: 8

Issue number: 12

Start page: 1954

End page: 1962

Number of pages: 9

ISSN: 1860-7179

eISSN: 1860-7187

Languages: English-Great Britain (EN-GB)

Unpaywall Data

Open access status: closed

Abstract

Three analogues of amythiamicinD, which differ in the substitution pattern at the methine group adjacent to C2 of the thiazole ringC, were prepared by denovo total synthesis. In amythiamicinD, this carbon atom is (S)-isopropyl substituted. Two of the new analogues carry a hydroxymethyl in place of the isopropyl group, one at an S- (compound 3a) and the other at an R-configured stereogenic center (3b). The third analogue, 3c, contains a benzyloxymethyl group at an S-configured stereogenic center. Compounds 3b and 3c showed no inhibitory effect toward various bacterial strains, nor did they influence the translation of firefly luciferase. In stark contrast, compound 3a inhibited the growth of Gram-positive bacteria Staphylococcus aureus (strains NCTC and Mu50) and Listeria monocytogenes EGD. In the firefly luciferase assay it proved more potent than amythiamicinD, and rescue experiments provided evidence that translation inhibition is due to binding to the bacterial elongation factor Tu (EF-Tu). The results were rationalized by structural investigations and by molecular dynamics simulations of the free compounds in solution and bound to the EF-Tu binding site. The low affinity of compound 3b was attributed to the absence of a critical hydrogen bond, which stabilizes the conformation required for binding to EF-Tu. Compound 3c was shown not to comply with the binding properties of the binding site.

Keywords

antibiotics, molecular modeling, natural products, protein biosynthesis, structure-activity relationships

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