AUTHOR=Porter Stephen B. , Johnston Brian D. , Kisiela Dagmara , Clabots Connie , Sokurenko Evgeni V. , Johnson James R. 

TITLE=Bacteriophage Cocktail and Microcin-Producing Probiotic Escherichia coli Protect Mice Against Gut Colonization With Multidrug-Resistant Escherichia coli Sequence Type 131

JOURNAL=Frontiers in Microbiology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2022.887799

DOI=10.3389/fmicb.2022.887799

ISSN=1664-302X

ABSTRACT=<p>Non-antibiotic measures are needed to reduce the rate of infections due to multidrug-resistant organisms (MDROs), including by eliminating the commensal reservoir that underlies such strains’ dissemination and leads to recurrent infections. Here, we tested a cocktail of pre-selected bacteriophages and an engineered microcin C7-producing probiotic <italic>Escherichia coli</italic> Nissle-1917 strain for their ability to reduce gut colonization by an <italic>E. coli</italic> strain from sequence type 131 (ST131)-<italic>H</italic>30R, which is the major clonal group of MDROs among extraintestinal clinical <italic>E. coli</italic> isolates. Although the bacteriophage cocktail was highly effective against ST131-<italic>H</italic>30R strains both <italic>in vitro</italic> and in a murine model of subcutaneous sepsis, it was only weakly and transiently effective against gut colonization by the target ST131-<italic>H</italic>30R strain (0.5 log<sub>10</sub> decrease on <italic>d</italic> + 1: <italic>p</italic> &lt; 0.001; no significant effect on <italic>d</italic> + 4 and beyond). The probiotic strain, while also highly active against ST131-<italic>H</italic>30R <italic>in vitro</italic>, was ineffective against ST131-<italic>H</italic>30R gut colonization despite its abundant presence in feces. Nonetheless, despite failing as decolonizing agents when administered separately, when co-administered the bacteriophage cocktail and probiotic strain exhibited striking synergy against ST131-<italic>H</italic>30R gut colonization. This combinatory effect was most pronounced on <italic>d</italic> + 1 (3.3 log<sub>10</sub> target strain decrease: <italic>p</italic> &lt; 0.001), and persisted until <italic>d</italic> + 7 (0.5 log<sub>10</sub> decrease; <italic>p</italic> &lt; 0.02.). Although by <italic>d</italic> + 10 the ST131-<italic>H</italic>30R load was fully restored, these findings provide proof of concept for combined bacteriophage-plus-probiotic administration to reduce or, possibly, to prevent gut colonization with MDROs in high-risk individuals.</p>