AVOGADRO

Adapting Versatile Opportunities for Glycopeptide Antibiotics against Drug-Resistant Organisms

01/04/2025 to 31/03/2028

Glycopeptide antibiotics (GPAs), e.g. vancomycin, are key therapeutics in the fight against gram-positive
pathogens. However, the emergence of vancomycin resistance demonstrates the need for innovative
strategies to combat antibiotic resistance. GPAs exhibit remarkable structural diversity and biosynthetic
complexity, involving non-ribosomal peptide synthetases (NRPSs), oxidative cascades, and post-synthetic
modifications. Recent advances in computational analysis and genomic mining have enabled a
comprehensive exploration of GPA biosynthetic gene clusters (BGCs). Our consortium aims to generate
uniquely modified GPAs with enhanced and broader antibacterial activity against resistant strains in an
iterative process. Key objectives include mining of actinobacterial genomes for novel GPA BGCs and
modification enzymes. Production of newly identified GPA candidates, followed by molecular dynamics
simulations of their interaction with the target lipid II, will reveal key sites for further GPA engineering through
the activity of newly identified modification enzymes, first in vitro and then in a GPA producer strain. For the
resulting new GPA derivatives, analysis of site-specific binding to resistant lipid II will be performed with
advanced NMR techniques, and bioactivity against a tester strain will be confirmed. Finally, bioactivity
profiling will validate the efficacy of the engineered GPA derivatives towards a range of resistant clinical
isolates. We expect this collaborative interdisciplinary effort to deliver next-generation GPAs to address
antibiotic resistance.