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, determined by spotting the same dilutions onto LB agar plates covered with a bacterial lawn of 553

, the host strain and supplemented with the appropriate antibiotics. The plates were incubated 554 for 18 hrs at 37°C. The detection limit was 5 x 10 2 cfu or pfu per millilitre of culture or gram of 555 faeces

, Host range of adapted bacteriophages 558

, Ad_P10 (n=16) were tested for infectivity, as described above, against different E. coli strains 559 (n=105)

, Analysis of genomic sequences 562

, Sequencing of bacteriophages and bacteriophage populations (study accession number 563 PRJEB18073) was performed using Illumina sequencing technology, Illumina Inc, p.564

C. , Bacteriophage DNA was extracted from a sterile bacteriophage solution, p.565

, For bacteriophage sequence analysis, the quality of Illumina reads was 567 visualised by FastQC v0, Bacteriophage assembly was 569 performed using a workflow implemented in Galaxy-Institut Pasteur using clc_assembler v4, 2009.

, P10 annotation was performed by the RAST v2, CLC Bio, vol.4, issue.20

A. , For synteny analysis, we aligned all the 572 contigs of phage genomes using blastn v2.2.18 (Altschul et al., 1990) (with option ?F F) against 573 the sequence of P10, Artemis Comparison Tool, 2005.

, synteny and for detection of recombination. No other bacteriophage than P10 was ever 575 purified and sequenced from amplification on strains LF82 or, 1655.

, ) 578 and looked for homologous regions in all annotated tail fiber sequences within each 579 bacteriophage genome using megablast blastn v2.2.18 (with option ?F F) Genome mutations 580 were identified using the BRESEQ Variant Report -v0, For researching hIGR events in other bacteriophage genomes, we downloaded the annotation 577 of all bacteriophages available on PhAnToMe, 2009.

, Bacteriophage recombination 584

, An adenine to guanidine substitution at nucleotide position 55079 of P10 genome was 585 introduced in the gp91 gene by site-directed mutagenesis using Polymerase Chain Reaction 586 (PCR) The mutated gene was cloned as an EcoRI-XbaI fragment in plasmid pUC18 (Norrander et 587 al., 1983) and transformed into LF82. P10 was added to a culture of LF82, carrying such plasmid 588 (or an empty plasmid as control), in early logarithmic growth phase, at an M.O.I. of 0, growing with strain MG1655 in equal proportions to enrich the recombinant population. A 590, p.589

, lysate recovered after 4 hrs incubation at 37°C was plated on a lawn of either strain LF82 or 591 MG1655 to recover ad_P10 plaques. Presence of the mutation was confirmed by PCR, p.20

, 592 plaques isolated on MG1655 and following three rounds of purification

, Bacteriophage fitness test, vol.596, p.31

, Gp91 protein compared to the wild type P10 bacteriophage was measured as 598 follows. First, rP10 was replicated on the MG1655 strain during four cycles of four hours at 599 multiplicity of infection (M.O.I.) = 0.001. The resulting bacteriophage lysate was named rP10 600 [MG]. Then, P10, rP10 and rP10 [MG] were added to exponentially growing cultures at 601 OD600=0.2 of either strains LF82 + MG1655, LF82 + MEc1 or MEc1 + MG1655 mixed in equal 602 proportions and at M.O.I. = 0.01. A negative control included the same amount of 603 bacteriophages mixed to growing medium only, The infection efficiency of the recombinant P10 bacteriophage (rP10) carrying the Y284H 597 mutation in the Co-cultures were incubated at 37°C statically 604 during 4 hrs and bacteriophages were titered on each of the bacterial strains. Data were 605 normalized as coefficient of multiplication compared to the initial bacteriophage inoculum. 606 Experiments were independently replicated three times and means were compared by 607 unpaired, p.one-tailed, t-test

, MEc1 isolation and sequencing 610

, Frozen feacal samples from streptomycin-treated control mice (not exposed to P10 or LF82 or, p.611

, MG1655) were serially diluted and plated aerobically onto Drigalski plates to select for possible, p.612

. Enterobacteriaceae, Isolated positive colonies were replicated in liquid cultures to approximate, p.613

. Saussereau, and 6 µL of culture were spotted onto agar plates and exposed to 1 x 10 5 pfu of P10 614 in a 4µL double spot assay, OD600=0.2 MEc1 was chosen as representative of 50, 2014.

, bacteriophage-sensitive colonies out of 60 Bacteriophage-bacteria co-culture was performed 616 as detailed above in the experimental conditions of coevolution, Genomic sequencing (study, p.32

, accession number PRJEB21810) was performed using Illumina technology, Illumina Inc, p.618

C. Diego,

. Quantification and . Statistical, ANALYSIS 621 Statistical analysis 622 Statistical analyses (Mann Whitney test and Student t-test) were conducted with Prism 5

, 623 software (GraphPad). p< 0.05 was considered statistically significant

, Sample size was determined by the " resource equation method, 1988.

, DATA AND SOFTWARE AVAILABILITY, vol.627

, The genomic sequences of bacteriophage P10, ad_P10 and rP10 as well as bacteriophage 628 populations have been deposited in the ENA under study accession number, 18073.

, The genomic sequence of strain MEc1 has been deposited in the ENA under study accession 630 number, 21810.