Scientists from the University of T?bingen and Monash University studied glycopeptide antibiotics, a key resource in countering drug-resistant pathogens, to uncover their evolutionary origins to gain insights that could led to the development of future antibiotics. They published their results ?Resurrecting ancestral antibiotics: unveiling the origins of modern lipid II targeting glycopeptides? in Nature Communications.

Using advanced bioinformatics, the team sought to decipher the chemical blueprint of ancient glycopeptide antibiotics.

?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,? write the investigators.

Molecule-centered approach

?Using a molecule-centered 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 optimization strategies nature has applied to evolve modern GPAs, laying the foundation for future efforts to engineer this important class of antimicrobial agents.?

Tracing an evolutionary path

Scientists often organize species into an evolutionary tree structure to illustrate their relationships. Similarly, the research team constructed a family tree of known glycopeptide antibiotics, linking their chemical structures via gene clusters that encode their blueprints. Employing bioinformatics algorithms, they deduced a putative ancestral form of these antibiotics, which they dubbed ?paleomycin.?

By reconstructing the genetic pathways, they believed to produce paleomycin, the team successfully synthesized the compound, which displayed antibiotic properties in tests. ?Recreating such an ancient molecule was exhilarating, akin to bringing dinosaurs or wooly mammoths back to life,? said Nadine Ziemert, PhD, associate professor at University of T?bingen.

?One intriguing finding is that all glycopeptide antibiotics stem from a common precursor,? added Evi Stegmann, PhD, a researcher at University of T?bingen.

?Moreover, the core structure of paleomycin mirrors the complexity seen in teicoplanin, while vancomycin exhibits a simpler core. We speculate that recent evolution streamlined the latter?s structure, yet its antibiotic function remained unchanged,? noted Ziemert.