Adapting Versatile Opportunities for Glycopeptide Antibiotics against Drug-Resistant Organisms

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.