Evaluating the potential efficacy and limitations of a phage for joint antibiotic and phage therapy of
            <i>Staphylococcus aureus</i>
            infections

Berryhill, Brandon A; Huseby, Douglas L.; McCall, Ingrid C.; Hughes, Diarmaid; Levin, Bruce R

doi:10.1073/pnas.2008007118

Cited by 53 publications

(53 citation statements)

References 49 publications

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“…This has implications for antibiotic-phage combination therapy, as it suggests that bacteriostatic antibiotics, which prevent bacterial growth, could reduce phage predation. This effect has been previously seen in S. aureus 37 .…”

Section: Discussionsupporting

confidence: 83%

The dual nature of bacteriophage: growth-dependent predation and generalised transduction of antimicrobial resistance

Leclerc

Wildfire

Gupta

et al. 2021

Preprint

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Bacteriophage ("phage") are both predators and evolutionary drivers for bacteria, notably contributing to the spread of antimicrobial resistance (AMR) genes by generalised transduction. Our current understanding of the dual nature of this relationship is limited. We used an interdisciplinary approach to quantify how these interacting dynamics can lead to the evolution of multi-drug resistant bacteria. We co-cultured two strains of Methicillin-resistant Staphylococcus aureus, each harbouring a different antibiotic resistance gene, with 80α generalized transducing phage. After a growth phase of 8h, bacteria and phage surprisingly coexisted at a stable equilibrium in our culture, the level of which was dependent on the starting concentration of phage. We detected double-resistant bacteria as early as 7h, indicating that transduction of AMR genes had occurred. We developed multiple mathematical models of the bacteria and phage relationship, and found that phage-bacteria dynamics were best captured by a model in which the phage burst size decreases as the bacteria population reaches stationary phase, and where phage predation is frequency-dependent. We estimated that one in every 108 new phage generated was a transducing phage carrying an AMR gene, and that double-resistant bacteria were always predominantly generated by transduction rather than by growth. Our results suggest a fundamental shift in how we understand and model phage-bacteria dynamics. Although rates of generalised transduction may seem insignificant, they are sufficient to consistently lead to the evolution of multi-drug resistant bacteria. Currently, the potential of phage to contribute to the growing burden of AMR is likely underestimated.

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Section: Discussionsupporting

confidence: 83%

The dual nature of bacteriophage: growth-dependent predation and generalised transduction of antimicrobial resistance

Leclerc

Wildfire

Gupta

et al. 2021

Preprint

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“…Furthermore, the development of phage resistance by modifying multi-drug efflux pump activity can increase the sensitivity to antibiotics [6]. A number of studies have already addressed the potential impact of a dual approach against S. aureus using a lytic phage in combination with MRSA-effective antibiotics, such as rifampicin, linezolid, fosfomycin, daptomycin, and vancomycin [7][8][9][10][11][12][13], as well as in combination with aminoglycosides, quinolone antibiotics, and β-lactam antibiotics [5,[11][12][13]. Interestingly, synergistic interactions between a phage and an antibiotic can also be observed in cases in which the pathogen is resistant against the antibiotic [14,15].…”

Section: Introductionmentioning

confidence: 99%

“…Phage Sb-1 has a broad host range, and due to its potential suitability for phage therapy, its biology and genomic features have been well studied over the years [20][21][22][23]. However, S. aureus can elude the entire phage-based clearance by several mechanisms (e.g., the formation of small-colony variants) [13]. Phage therapy would therefore greatly benefit from the possibility of co-treatment of a MRSA infection with an antibiotic.…”

Section: Introductionmentioning

confidence: 99%

Synergy between Phage Sb-1 and Oxacillin against Methicillin-Resistant Staphylococcus aureus

et al. 2021

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Methicillin-resistant Staphylococcus aureus (MRSA) is a notorious pathogen responsible for not only a number of difficult-to-treat hospital-acquired infections, but also for infections that are community- or livestock-acquired. The increasing lack of efficient antibiotics has renewed the interest in lytic bacteriophages (briefly phages) as additional antimicrobials against multi-drug resistant bacteria, including MRSA. The aim of this study was to test the hypothesis that a combination of the well-known and strictly lytic S. aureus phage Sb-1 and oxacillin, which as sole agent is ineffective against MRSA, exerts a significantly stronger bacterial reduction than either antimicrobial alone. Eighteen different MRSA isolates and, for comparison, five MSSA and four reference strains were included in this study. The bacteria were challenged with a combination of varying dosages of the phage and the antibiotic in liquid medium using five different antibiotic levels and four different viral titers (i.e., multiplicity of infections (MOIs) ranging from 10−5 to 10). The dynamics of the cell density changes were determined via time-kill assays over 16 h. Positive interactions between both antimicrobials in the form of facilitation, additive effects, or synergism were observed for most S. aureus isolates. These enhanced antibacterial effects were robust with phage MOIs of 10−1 and 10 irrespective of the antibiotic concentrations, ranging from 5 to 100 µg/mL. Neutral effects between both antimicrobials were seen only with few isolates. Importantly, antagonism was a rare exception. As a conclusion, phage Sb-1 and oxacillin constitute a robust heterologous antimicrobial pair which extends the efficacy of a phage-only approach for controlling MRSA.

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“…These phages display a broad host range, infecting most S. aureus isolates and even those of other staphylococcal species ( Lobocka et al., 2012 ). Studies on these group of phages and also their lytic enzymes hold promise for future clinical development alone or in combination with antibiotics ( Berryhill et al., 2021 ) especially as comparative genomic analysis show little similarity between phages from different lineages in gene complement or in their lytic gene sequences ( O’Flaherty et al., 2005a ; Synnott et al., 2009 ; Lobocka et al., 2012 ). These may therefore represent an important and diverse source of phages for traditional therapy or development of treatments based on novel antimicrobial enzymes.…”

Section: Introductionmentioning

confidence: 99%

Phenotypic and Genotypic Characterization of Novel Polyvalent Bacteriophages With Potent In Vitro Activity Against an International Collection of Genetically Diverse Staphylococcus aureus

Whittard

Redfern

Xia

et al. 2021

Front. Cell. Infect. Microbiol.

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Phage therapy recently passed a key milestone with success of the first regulated clinical trial using systemic administration. In this single-arm non-comparative safety study, phages were administered intravenously to patients with invasive Staphylococcus aureus infections with no adverse reactions reported. Here, we examined features of 78 lytic S. aureus phages, most of which were propagated using a S. carnosus host modified to be broadly susceptible to staphylococcal phage infection. Use of this host eliminates the threat of contamination with staphylococcal prophage — the main vector of S. aureus horizontal gene transfer. We determined the host range of these phages against an international collection of 185 S. aureus isolates with 56 different multilocus sequence types that included multiple representatives of all epidemic MRSA and MSSA clonal complexes. Forty of our 78 phages were able to infect > 90% of study isolates, 15 were able to infect > 95%, and two could infect all 184 clinical isolates, but not a phage-resistant mutant generated in a previous study. We selected the 10 phages with the widest host range for in vitro characterization by planktonic culture time-kill analysis against four isolates:- modified S. carnosus strain TM300H, methicillin-sensitive isolates D329 and 15981, and MRSA isolate 252. Six of these 10 phages were able to rapidly kill, reducing cell numbers of at least three isolates. The four best-performing phages, in this assay, were further shown to be highly effective in reducing 48 h biofilms on polystyrene formed by eight ST22 and eight ST36 MRSA isolates. Genomes of 22 of the widest host-range phages showed they belonged to the Twortvirinae subfamily of the order Caudovirales in three main groups corresponding to Silviavirus, and two distinct groups of Kayvirus. These genomes assembled as single-linear dsDNAs with an average length of 140 kb and a GC content of c. 30%. Phages that could infect > 96% of S. aureus isolates were found in all three groups, and these have great potential as therapeutic candidates if, in future studies, they can be formulated to maximize their efficacy and eliminate emergence of phage resistance by using appropriate combinations.

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Evaluating the potential efficacy and limitations of a phage for joint antibiotic and phage therapy of Staphylococcus aureus infections

Cited by 53 publications

References 49 publications

The dual nature of bacteriophage: growth-dependent predation and generalised transduction of antimicrobial resistance

The dual nature of bacteriophage: growth-dependent predation and generalised transduction of antimicrobial resistance

Synergy between Phage Sb-1 and Oxacillin against Methicillin-Resistant Staphylococcus aureus

Phenotypic and Genotypic Characterization of Novel Polyvalent Bacteriophages With Potent In Vitro Activity Against an International Collection of Genetically Diverse Staphylococcus aureus

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