Adapting Versatile Opportunities for Glycopeptide Antibiotics against Drug-Resistant Organisms
( AVOGADRO )

Interventions

Therapeutics

Research Project: 2025-04-01 - 2028-03-31
Total sum awarded: €1 443 271

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.

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  • Evi Stegmann, University of Tübingen, Germany (Coordinator)
  • Ziemert Nadine, University hospital of Tuebingen, Germany (Partner)
  • Olga Genilloud, Fundación Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía MEDINA, Spain (Partner)
  • Jozéf Lewandowski, University of Warwick, United Kingdom (Partner)
  • Max Cryle, Monash University, Australia (Partner)
  • Luis Martínez-Martínez, Hospital Universitario Reina Sofía, Spain (Partner)

Glycopeptide antibiotics (GPAs) are crucial in treating gram-positive bacterial infections, yet vancomycin-resistant bacteria pose challenges. GPAs are structurally diverse, synthesized via complex pathways involving the synthesis of the backbone and post-synthetic modifications. Recent computational and genomic advances allow comprehensive exploration of GPA biosynthesis. Our consortium seeks to develop enhanced GPAs by mining actinobacterial genomes for biosynthetic gene clusters, analysing their potential, and employing molecular dynamic simulations to understand interactions with resistant bacteria. In vitro studies will characterize modifying enzymes' impact, while synthetic biology enables precise modifications and production of the modified GPAs. Advanced NMR techniques will analyse site-specific binding to resistant bacteria, and bioactivity profiling will validate efficacy. This collaborative effort offers a multidisciplinary approach to combat antibiotic resistance. This collaborative effort represents a multidisciplinary approach to combat antibiotic resistance. By identifying and producing next-generation GPAs, we aim to stay one step ahead of evolving bacterial threats and safeguard public health.

Call

2024 - Interventions moving forward to promote action to counteract the emergence and spread of bacterial and fungal resistance and to improve treatments