Tackling Multidrug-Resistant E. coli: A Dual Strike Approach using a phage cocktail and a host-targeting molecule

The multidrug resistant (MDR) Escherichia coli ST131 isolates are dominant extraintestinal pathogenic E. coli (ExPEC) with an increased capacity to colonize the gut, form intestinal reservoirs, and invade tissues. The CNF1 toxin expressed by these strains is a gut colonization factor involved in intestinal tissue invasion. Recently, the C910 compound was found to block CNF1-mediated host cell invasion1.

The use of bacteriophages to reduce gut colonization of enteric pathogens has shown weak to moderate efficacy2. We hypothesise that a double edge sword strategy based on the combination of bacteriophages with the C910 compound may enhance the clearance of enteric pathogens.

To setup the combined treatment, we first screened our phage collection and extensively assessed their activity in vitro to finally choose a cocktail of three genetically different phages. We found that the efficacy of this cocktail combined with the C910 molecule on epithelial cells infected with an ST131 isolate was synergistic, compared to individual treatments. Next, we used OMM12 mice, a gnotobiotic mouse model housing and transmitting a stable population of 12 bacteria and 11 induced prophages to evaluate the combined treatment in vivo3. Following the characterization of the gut colonization profile of the ST131 isolate, including its capacity to form intracellular reservoir in the gut epithelium, we tested the combined treatment and observed an improved efficacy.