Combination of in vivo phage therapy data with in silico model highlights key parameters for pneumonia treatment efficacy

Delattre, Raphaëlle; Seurat, Jérémy; F, Haddad; Nguyen, Thu-Thuy; Gaborieau, Baptiste; Kane, Rokhaya; Dufour, Nicolas; Ricard, Jean‐Damien; Guedj, Jérémie; Debarbieux, Laurent

doi:10.1016/j.celrep.2022.110825

Cited by 24 publications

(24 citation statements)

References 52 publications

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“…This suggests that the animal host does not influence this selection process. However, the acute pneumonia model imposes limitations such as the use of a large bacterial population to initiate a fatal infection by overwhelming the immune system, as well as a large phage dose to provide a rapid and efficient treatment (48). It then remains possible that a putative impact of the animal host on phage resistance mechanisms could not been detected within this setting and may require extended time of observation.…”

Section: Discussionmentioning

confidence: 99%

Variable effects on virulence of bacteriophage resistance mechanisms in extraintestinal pathogenicEscherichia coli

Gaborieau

Delattre

Adiba

et al. 2022

Preprint

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Bacteria exposed to killing agents such as antibiotics or viruses develop resistance. While phage therapy, the use of bacteriophages (phages) for treating bacterial infections, is proposed to answer the antibiotic resistance crisis, bacterial resistance to phages remains poorly characterized during phage treatment. We studied a large population of phage-resistant extra-intestinal pathogenic Escherichia coli 536 clones emerging from both in vitro (non-limited liquid medium) and in vivo (murine pneumonia) conditions. Genome sequencing revealed a mutational convergence of phage resistance mechanisms towards the modification of two cell-wall components, the K15 capsule and the LPS, whatever the condition, showing that their identification could be predicted from the in vitro conditions. The fitness cost of all phage resistant clones was broad in terms of growth rate and resistance to grazing by amoeba and could not discriminate K15 capsule to LPS mutants. By contrast, the virulence of the clones tested in mice showed that K15 capsule mutants were as virulent as the wildtype strain while LPS mutants were strongly attenuated. We also found that resistance to one phage led to the sensitization to other phages. In clinics, to control phage-resistant clones that remains virulent phage cocktail should include phages infecting both phage susceptible and future phage resistant clones.

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Section: Discussionmentioning

confidence: 99%

Variable effects on virulence of bacteriophage resistance mechanisms in extraintestinal pathogenicEscherichia coli

Gaborieau

Delattre

Adiba

et al. 2022

Preprint

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“…Another limitation is the lack of loss of phages over time as they remained trapped in the same compartment of bacteria. However, the decay of phages in uninfected or infected lungs of mice was shown to be rather weak (below 1-log per day) compared to the overall density of phages in the HFIM [30]. The data presented here advocate in favor of a translation to clinics that could ultimately slow down the use of multiple antibiotics and therefore, the selection of MDR strains [17].…”

Section: Discussionmentioning

confidence: 99%

The selection of antibiotic- and bacteriophage-resistant Pseudomonas aeruginosa is prevented by their combination

Ferran

Lacroix

Gourbeyre

et al. 2022

Preprint

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Objectives: Bacteria developing resistance compromise the efficacy of antibiotics or bacteriophages (phages). We tested the association of these two antibacterials to circumvent resistance. Methods: With the Hollow Fiber Infection Model (HFIM), we mimicked the concentration profile of ciprofloxacin in the lungs of patients treated orally for Pseudomonas aeruginosa infections and independently, mimicked a single inhaled administration of phages (one or two phages). Results: Each treatment selects for antibiotic- or phage-resistant clones in less than 30 h. By contrast, no bacteria were recovered from the HFIM at 72 h when ciprofloxacin was started 4 h post-phage administration, even when increasing the initial bacterial concentration by a 1000 fold. Conclusion: The combination of phages with antibiotics used according to clinical regimens prevents the growth of resistant clones, providing opportunities to downscale the use of multiple antibiotics.

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“…Mathematical models are crucial tools in advancing our design of phage therapies ( Payne and Jansen 2001 ; Cairns et al. 2009 ; Delattre et al. 2022 ) by allowing us to extend molecular knowledge to population dynamics predictions.…”

Section: What Does Phenotypic Flux Mean For Phage Therapy?mentioning

confidence: 99%

Phenotypic flux: The role of physiology in explaining the conundrum of bacterial persistence amid phage attack

Igler

2022

Virus Evolution

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Bacteriophages, the viruses of bacteria, have been studied for over a century. They were not only instrumental in laying the foundations of molecular biology, but they likely play crucial roles in shaping our biosphere and may offer a solution to the control of drug-resistant bacterial infections. Yet, it remains challenging to predict the conditions for bacterial eradication by phage predation, sometimes even under well-defined laboratory conditions, and, most curiously, if the majority of surviving cells are genetically phage-susceptible. Here, I propose that even clonal phage and bacterial populations are generally in a state of continuous ‘phenotypic flux’, which is caused by transient and non-genetic variation in phage and bacterial physiology. Phenotypic flux can shape phage infection dynamics by reducing the force of infection to an extent that allows for co-existence between phages and susceptible bacteria. Understanding the mechanisms and impact of phenotypic flux may be key to providing a complete picture of phage-bacteria co-existence. I review the empirical evidence for phenotypic variation in phage and bacterial physiology together with the ways they have been modelled, and discuss the potential implications of phenotypic flux for ecological and evolutionary dynamics between phages and bacteria as well as for phage therapy.

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Combination of in vivo phage therapy data with in silico model highlights key parameters for pneumonia treatment efficacy

Cited by 24 publications

References 52 publications

Variable effects on virulence of bacteriophage resistance mechanisms in extraintestinal pathogenicEscherichia coli

Variable effects on virulence of bacteriophage resistance mechanisms in extraintestinal pathogenicEscherichia coli

The selection of antibiotic- and bacteriophage-resistant Pseudomonas aeruginosa is prevented by their combination

Phenotypic flux: The role of physiology in explaining the conundrum of bacterial persistence amid phage attack

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