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bioRxiv · 10.1101/2023.02.10.526856

Phylogenetic distance and structural diversity directing a reclassification of glycopeptide antibiotics

Gavriilidou, A.·Adamek, M.·Rodler, J.-P.·Kubach, N.·Kremer, S.·Huson, D.·Cryle, M.·Stegmann, E.·Ziemert, N.
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Abstract

Glycopeptide antibiotics (GPAs) are key agents against multidrug-resistant Gram-positive pathogens, yet both the term "glycopeptide" and the current GPA type I-V classification framework have become increasingly strained as structurally and mechanistically divergent members continue to be discovered. In particular, compounds historically grouped as "type V GPAs" differ from classical GPAs in features such as glycosylation, peptide length, and reported mode of action, raising the question of whether they belong to the same natural product class. Here, a curated dataset of GPA-associated biosynthetic gene clusters (BGCs) is analysed by combining fingerprint similarity of the products with phylogenetic analysis of the BGCs. Fingerprint-based structural similarity networks and BGC similarity comparisons reveal a pronounced separation between classical lipid II-binding GPAs (types I-IV) and type V GPAs. Multi-locus phylogenetic analyses of conserved biosynthetic components further support two deeply divergent evolutionary subclasses, consistent with subclass-specific biosynthetic signatures. Together, these results motivate a revised, unambiguous framework in which the broader class is termed xyclopeptides, comprising the subclasses dalabactins (legacy GPA types I-IV) and murobactins (legacy type V).

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Gavriilidou, A., Adamek, M., Rodler, J.-P., Kubach, N., Kremer, S., Huson, D., Cryle, M., Stegmann, E., Ziemert, N.. 2023-02-11. Phylogenetic distance and structural diversity directing a reclassification of glycopeptide antibiotics. https://doi.org/10.1101/2023.02.10.526856

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