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.
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.
- 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
Multidrug-resistant bacterial infections are increasingly common, and the trickling pipeline of new antibiotics can do little to stem the tide. Instead, entirely new types of antibiotics are needed. One promising avenue involves CRISPR. CRISPR is best known for genome editing and a means to reverse genetic diseases. However, this same tool also be used to eliminate multidrug resistant pathogens while sparing commensal bacteria inhabiting our bodies. Early work highlighted the promise of these CRISPR antimicrobials, yet it remains a fledgling technology that requires further development before being ready for the clinic.
Through funding from JPIAMR, we are developing CRISPR antimicrobials against Klebsiella pneumoniae, a major cause of multidrug resistant infections worldwide. These pathogens often spread in hospitals and can be resistant to virtually every antibiotic at our disposal. Our goals are to deliver CRISPR to these bacteria using bacterial viruses called bacteriophages and ensure CRISPR can eliminate cells carrying antibiotic resistance. Toward this goal, we have assembled a team of experts in CRISPR biology and technologies, bacteriophage engineering, and Klebsiella. The team has been engineering bacteriophages as vehicles to deliver the CRISPR cargo to different Klebsiella strains found in hospitals. We have also been identifying the best CRISPR enzymes that eradicate cells with target sequences.
Finally, we are working toward experiments in mice that will lay a path toward clinical trials. The resulting optimized CRISPR antimicrobials will represent a leap forward toward the commercial development of novel antimicrobials against Klebsiella, and they will allow us to develop similar CRISPR antimicrobials against other multi-drug resistant pathogens. Through these efforts, we aim to provide new weapons against bacterial infections and turn the tide of antibiotic resistance.
- Scientific Reports, 2020. A continuous evolution system for contracting the host range of bacteriophage T7