8GLC

A1 AncAla: Adenylation domain 1 core construct from ancestral reconstruction of glycopeptide antibiotic biosynthesis, alanine selection pocket

Summary for 8GLC

• Entry DOI: 10.2210/pdb8glc/pdb
• Descriptor: Non-ribosomal peptide synthetase, MbtH-like short polypeptide (2 entities in total)
• Functional Keywords: amp-binding enzyme, nrps, adenylation domain, ligase
• Biological source: Actinoplanes; More
• Total number of polymer chains: 4
• Total formula weight: 100599.50

Authors

Hansen, M.H.,Cryle, M.J. (deposition date: 2023-03-21, release date: 2023-12-06, Last modification date: 2023-12-13)

Primary citation

Hansen, M.H.,Adamek, M.,Iftime, D.,Petras, D.,Schuseil, F.,Grond, S.,Stegmann, E.,Cryle, M.J.,Ziemert, N.
Resurrecting ancestral antibiotics: unveiling the origins of modern lipid II targeting glycopeptides.
Nat Commun, 14:7842-7842, 2023

PubMed Abstract: Antibiotics are central to modern medicine, and yet they are mainly the products of intra and inter-kingdom evolutionary warfare. To understand how nature evolves antibiotics around a common mechanism of action, we investigated the origins of an extremely valuable class of compounds, lipid II targeting glycopeptide antibiotics (GPAs, exemplified by teicoplanin and vancomycin), which are used as last resort for the treatment of antibiotic resistant bacterial infections. Using a molecule-centred approach and computational techniques, we first predicted the nonribosomal peptide synthetase assembly line of paleomycin, the ancestral parent of lipid II targeting GPAs. Subsequently, we employed synthetic biology techniques to produce the predicted peptide and validated its antibiotic activity. We revealed the structure of paleomycin, which enabled us to address how nature morphs a peptide antibiotic scaffold through evolution. In doing so, we obtained temporal snapshots of key selection domains in nonribosomal peptide synthesis during the biosynthetic journey from ancestral, teicoplanin-like GPAs to modern GPAs such as vancomycin. Our study demonstrates the synergy of computational techniques and synthetic biology approaches enabling us to journey back in time, trace the temporal evolution of antibiotics, and revive these ancestral molecules. It also reveals the optimisation strategies nature has applied to evolve modern GPAs, laying the foundation for future efforts to engineer this important class of antimicrobial agents.

PubMed: 38030603
DOI: 10.1038/s41467-023-43451-4

Experimental method

X-RAY DIFFRACTION (3.12 Å)