Advancing CRISPR antimicrobials to combat the bacterial pathogen Klebsiella pneumoniae (CRISPRattacK)

The increasing incidence of multidrug-resistant bacterial infections and the trickling pipeline of novel antibiotic classes demand a new generation of antimicrobials. One promising avenue has been the development of antimicrobials based on CRISPR-Cas immune systems.

Ongoing project

These systems can be programmed to specifically and efficiently eliminate cells harbouring multi-drug resistance genes without impinging on resident microbiota. However, CRISPR antimicrobials remain to be advanced from a few proof-of-principle demonstrations to established therapeutics that can effectively combat the most pressing pathogens. Here, we propose to advance this antimicrobial platform to selectively kill Klebsiella pneumoniae, a major cause of multi-drug resistant, nosocomial infections worldwide.

We have devised a series of experimental approaches that will identify the most active CRISPR nucleases and DNA target sites for programmed killing, engineer bacteriophage delivery vehicles that can efficiently deliver CRISPR to a large fraction of clinical isolates, and evaluate the efficacy of the most promising therapeutic candidates in mouse infection models. Once demonstrated, the resulting optimised CRISPR antimicrobials will represent a large leap forward for the development of novel antimicrobials against Klebsiella, and they will provide a framework to develop similar antimicrobials against other high-priority pathogens associated with multidrug resistance.

 

Project partners

  • Chase Beisel, Helmholtz Centre for Infection Research, Germany (Coordinator)
  • Udi Qimron, Tel-Aviv University, Israel
  • David Bikard, Pasteur Institute, France
  • Sylvain Brisse, Pasteur Institute, France
  • Strowig Till, Helmholtz Centre for Infection Research, Germany