Bacteriophage LM33_P1, a fast-acting weapon against the pandemic ST131-O25b:H4Escherichia coliclonal complex

<st>Objectives</st> Amongst the highly diverse <it>Escherichia coli</it> population, the ST131-O25b:H4 clonal complex is particularly worrisome as it is associated with a high level of antibiotic resistance. The lack of new antibiotics, the worldwide continuous increase of infections caused by MDR bacteria and the need for narrow-spectrum antimicrobial agents have revived interest in phage therapy. In this article, we describe a virulent bacteriophage, LM33_P1, which specifically infects O25b strains, and provide data related to its therapeutic potential. <st>Methods</st> A large panel of <it>E. coli</it> strains (<it>n</it> = 283) was used to assess both the specificity and the activity of bacteriophage LM33_P1. Immunology, biochemistry and genetics-based methods confirmed this specificity. Virology methods and sequencing were used to characterize this bacteriophage <it>in vitro</it>, while three relevant mouse models were employed to show its <it>in vivo</it> efficacy. <st>Results</st> Bacteriophage LM33_P1 exclusively infects O25b <it>E. coli</it> strains with a 70% coverage on sequence types associated with high antibiotic resistance (ST131 and ST69). This specificity is due to an interaction with the LPS mediated by an original tail fibre. LM33_P1 also has exceptional intrinsic properties with a high adsorption constant and produces over 300 virions per cell in <10 min. Using animal pneumonia, septicaemia and urinary tract infection models, we showed the <it>in vivo</it> efficacy of LM33_P1 to reduce the bacterial load in several organs. <st>Conclusions</st> Bacteriophage LM33_P1 represents the first weapon that specifically and quickly kills O25b <it>E. coli</it> strains. Therapeutic approaches derived from this bacteriophage could be developed to stop or slow down the spread of the ST131-O25b:H4 drug-resistant clonal complex in humans.