Informing genomic surveillance by uncovering, phenotyping and prioritising resistance genes to new antibiotics
( NewResGenes )

Environment

Surveillance

Research Project: 2024-04-01 - 2027-03-31
Total sum awarded: €1 431 258

Understanding the genetic and phenotypic diversity of antimicrobial resistance genes (ARGs) in One Health settings, throughout the environment, agriculture and clinics, is crucial for genomics-based surveillance of antimicrobial resistance (AMR). While much knowledge is being gained on the spread of known clinical ARGs, there is still a lack of systematic approaches to identify the resistance phenotypes of novel ARGs and how they disseminate into populations of pathogens. This major knowledge gap – especially substantial in the case of new antibiotics which are currently in clinical development – precludes our ability to detect and slow down the emergence of resistance. Here, we develop novel methods to discover, characterise and prioritise ARGs using a One Health approach to support genomic surveillance efforts world-wide. Specifically, we will systematically identify thousands of ARGs against multiple classes of novel and already widely used antibiotics in a diverse set of One Health settings using a combination of functional metagenomic screens, high-throughput gene synthesis, and genome-wide association studies. We will then experimentally characterise such ARGs in three of the most critical Gram-negative pathogens and rank them based on their risk of resistance dissemination using novel bioinformatics methods. This proof-of-concept study will provide integrated genomic and phenotypic reference data on ARGs against novel antibiotics and give the biomedical community guidelines on how to track and diminish the emergence of resistance.

Read More
Read Less
  • Balint Kintses, Biological Research Centre of ELKH, Hungary (Coordinator)
  • Fiona Walsh, Maynooth University, Ireland (Partner)
  • Nobuhiko Tokuriki, University of British Columbia, Canada (Partner)
  • Balázs Papp, Biological Research Centre of ELKH, Hungary (Partner)
  • Eduardo Rocha, Institut Pasteur, France (Partner)
  • Anne Farewell, University of Gothenburg, Sweden (Partner)

The majority of current resistance problems encountered in clinical practice start with the mobilisation of antibiotic resistance genes (ARGs) from the environment into clinical pathogens. Therefore, the pace at which a novel antibiotic will face resistance largely depends on how widespread the ARGs are and how easily they can be mobilised into the target bacteria to compromise the effect of the antibiotic. However, when it comes to antibiotics that are new on the market, we have little prior knowledge on which ARGs are going to be active against them. Such ARGs are usually spotted by clinicians when they have already become widespread among clinical pathogens. Here we propose novel experimental and computational methods to functionally annotate ARGs at an unprecedented scale and estimate the mobilisation potential of the found ARGs into target pathogens before they have spread widely. As a proof of concept study, we are going to investigate a diverse set of One Health settings for the potential to provide ARGs against future antibiotics for human use – those that are currently in clinical development. Furthermore, to expand our knowledge of ARGs for existing antibiotics, we are going to carry out the same experiments with a set of antibiotics that has been applied for decades. The advanced features of the proposed pipeline will provide accurate assessments of the risks and possible routes of emerging resistance from an early phase. The ultimate goal is to inform world-wide genomic surveillance efforts on how to better track the emergence and spread of resistance.

Call

2023 - Development of innovative strategies, tools, technologies, and methods for diagnostics and surveillance of antimicrobial resistance