New gene-edited drug targets bacteria, bringing hope to cancer treatment

The study published in the journal Nature biotechnology explained: “Translocation of gut bacteria, including Escherichia coli, from the gastrointestinal tract is a frequent cause of bloodstream infections. The mortality related to bloodstream infections caused by enteric bacteria such as E. coli is 15–20 percent; to decrease the chance of infection, antibiotics may be given before treatment in people at risk of low numbers of neutrophils in the blood.” 

The development of the drug

The team used engineered bacteriophages for this drug development. Bacteriophages are viruses that specifically target bacteria, making their behavior selective.

According to the study, nearly 162 phages were screened to find those capable of infecting a wide range of E. coli strains derived from humans. The strains were obtained from people who had bloodstream or urinary tract infections and from healthy people's guts.

After this step, the phages were engineered using CRISPR to target the E. coli genome. A total of eight engineered phages were chosen, and a combination of four of these was found to be most effective against E. coli. SNIPR001 is the name given to this group of four mixtures. 

The drug was tested in mice models by administering it orally. The results showed that there was less E. coli in the feces and that it was not resistant to the phage cocktail. The results demonstrated that this technique could prevent bacterial resistance. 

E. coli is responsible for many bacterial infections in cancer patients. It has also been discovered to resist fluoroquinolones, the antibiotics used to treat such infections.

Study abstract:

Antibiotic treatments have detrimental effects on the microbiome and lead to antibiotic resistance. To develop a phage therapy against a diverse range of clinically relevant Escherichia coli, we screened a library of 162 wild-type (WT) phages, identifying eight phages with broad coverage of E. coli, complementary binding to bacterial surface receptors, and the capability to stably carry inserted cargo. Selected phages were engineered with tail fibers and CRISPR–Cas machinery to specifically target E. coli. We show that engineered phages target bacteria in biofilms, reduce the emergence of phage-tolerant E. coli and out-compete their ancestral WT phages in coculture experiments. A combination of the four most complementary bacteriophages, called SNIPR001, is well tolerated in both mouse models and minipigs and reduces E. coli load in the mouse gut better than its constituent components separately. SNIPR001 is in clinical development to selectively kill E. coli, which may cause fatal infections in hematological cancer patients.