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Three New Escherichia coli Phages from the Human Gut Show Promising Potential for Phage Therapy.

ABSTRACT: With the emergence of multi-drug resistant bacteria the use of bacteriophages (phages) is gaining renewed interest as promising anti-microbial agents. The aim of this study was to isolate and characterize phages from human fecal samples. Three new coliphages, ?APCEc01, ?APCEc02 and ?APCEc03, were isolated. Their phenotypic and genomic characteristics, and lytic activity against biofilm, and in combination with ciprofloxacin, were investigated. All three phages reduced the growth of E. coli strain DPC6051 at multiplicity of infection (MOI) between 10-3 and 105. A cocktail of all three phages completely inhibited the growth of E. coli. The phage cocktail also reduced biofilm formation and prevented the emergence of phage-resistant mutants which occurred with single phage. When combined with ciprofloxacin, phage alone or in cocktail inhibited the growth of E. coli and prevented the emergence of resistant mutants. These three new phages are promising biocontrol agents for E. coli infections.

SUBMITTER: Dalmasso M

PROVIDER: S-EPMC4900583 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Three New Escherichia coli Phages from the Human Gut Show Promising Potential for Phage Therapy.

Dalmasso Marion M Strain Ronan R Neve Horst H Franz Charles M A P CM Cousin Fabien J FJ Ross R Paul RP Hill Colin C

PloS one 20160609 6

With the emergence of multi-drug resistant bacteria the use of bacteriophages (phages) is gaining renewed interest as promising anti-microbial agents. The aim of this study was to isolate and characterize phages from human fecal samples. Three new coliphages, ɸAPCEc01, ɸAPCEc02 and ɸAPCEc03, were isolated. Their phenotypic and genomic characteristics, and lytic activity against biofilm, and in combination with ciprofloxacin, were investigated. All three phages reduced the growth of E. coli strai ...[more]

PMID: 27280590

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Project description:BACKGROUND:Shiga toxin-producing Escherichia coli O157:H7 is a foodborne pathogen that causes severe human diseases including hemolytic uremic syndrome (HUS). The virulence factor that mediates HUS, Shiga toxin (Stx), is encoded within the genome of a lambdoid prophage. Although draft sequences are publicly available for a large number of E. coli O157:H7 strains, the high sequence similarity of stx-converting bacteriophages with other lambdoid prophages poses challenges to accurately assess the organization and plasticity among stx-converting phages due to assembly difficulties. METHODS:To further explore genome plasticity of stx-converting prophages, we enriched phage DNA from 45 ciprofloxacin-induced cultures for subsequent 454 pyrosequencing to facilitate assembly of the complete phage genomes. In total, 22 stx2a-converting phage genomes were closed. RESULTS:Comparison of the genomes distinguished nine distinct phage sequence types (PSTs) delineated by variation in obtained sequences, such as single nucleotide polymorphisms (SNPs) and insertion sequence element prevalence and location. These nine PSTs formed three distinct clusters, designated as PST1, PST2 and PST3. The PST2 cluster, identified in two clade 8 strains, was related to stx2a-converting phages previously identified in non-O157 Shiga-toxin producing E. coli (STEC) strains associated with a high incidence of HUS. The PST1 cluster contained phages related to those from E. coli O157:H7 strain Sakai (lineage I, clade 1), and PST3 contained a single phage that was distinct from the rest but most related to the phage from E. coli O157:H7 strain EC4115 (lineage I/II, clade 8). Five strains carried identical stx2a-converting phages (PST1-1) integrated at the same chromosomal locus, but these strains produced different levels of Stx2. CONCLUSION:The stx2a-converting phages of E. coli O157:H7 can be categorized into at least three phage types. Diversification within a phage type is mainly driven by IS629 and by a small number of SNPs. Polymorphisms between phage genomes may help explain differences in Stx2a production between strains, however our data indicates that genes encoded external to the phage affect toxin production as well.

Project description:The growing resistance of bacteria to antibiotics is a major global public health concern. An important reservoir of this resistance is the gut microbiota. However, limited data are available on the ability of phage therapy to reduce the digestive carriage of multidrug-resistant bacteria. Four novel lytic phages were isolated in vitro for efficacy against an extended-spectrum beta-lactamase-producing (ESBL) Escherichia coli strain also resistant to carbapenems through a carbapenemase OXA-48. The first step was to develop models of ESBL E. coli digestive carriage in mice. The second step was to test the efficacy of an oral and rectal phage therapy (a cocktail of four phages or microencapsulated phage) to reduce this carriage. The two most intense models of digestive carriage were obtained by administering amoxicillin (0.5 g·L-1) continuously in the drinking water (Model 1) or pantoprazole (0.1 g·L-1) continuously in the drinking water, combined with amoxicillin (0.5 g·L-1), for the first 8 days (Model 2). Oral administration of the phage cocktail to Model 1 resulted in a transient reduction in the concentration of ESBL E. coli in the faeces 9 days after the bacterial challenge (median = 5.33 × 108 versus 2.76 × 109 CFU·g-1, p = 0.02). In contrast, in Model 2, oral or oral + rectal administration of this cocktail did not alter the bacterial titre compared to the control (area under the curve, AUC, 3.49 × 109; 3.41 × 109 and 3.82 × 109 for the control, oral and oral + rectal groups, respectively; p-value > 0.8 for each two-by-two group comparison), as well as the administration of an oral microencapsulated phage in Model 1 (AUC = 8.93 × 109 versus 9.04 × 109, p = 0.81). Oral treatment with amoxicillin promoted digestive carriage in mice, which was also the case for the addition of pantoprazole. However, our study confirms the difficulty of achieving efficacy with phage therapy to reduce multidrug-resistant bacterial digestive carriage in vivo.

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Three New Escherichia coli Phages from the Human Gut Show Promising Potential for Phage Therapy.

Publications

Three New Escherichia coli Phages from the Human Gut Show Promising Potential for Phage Therapy.

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