Promises and pitfalls of<i>in vivo</i>evolution to improve phage therapy

In response to increasing frequencies of antibiotic-resistant pathogens, there has been a resurrection of interest in the use of bacteriophage to treat bacterial infections: phage therapy. Here we explore the potential of a seemingly ideal phage, PYOSa, for combination phage and antibiotic treatment of Staphylococcus aureus infections. This K-like phage has a broad host range; all 83 tested clinical isolates of S.aureus tested were susceptible to PYOSa. Because of the mode of action of PYOSa, S. aureus is unlikely to generate classical receptor-site mutants resistant to PYOSa; none were observed in the 13 clinical isolates tested. PYOSa kills S. aureus at high rates. On the downside, the results of our experiments and tests of the joint action of PYOSa and antibiotics raise issues that must be addressed before PYOSa is employed clinically. Despite the maintenance of the phage, PYOSa does not clear populations of S. aureus. Due to the ascent of a phenotyically diverse array of small-colony variants following an initial demise, the bacterial populations return to densities similar to that of phage-free controls. Using a combination of mathematical modeling and in vitro experiments, we postulate and present evidence for a mechanism to account for the demise–resurrection dynamics of PYOSa and S. aureus. Critically for phage therapy, our experimental results suggest that treatment with PYOSa followed by bactericidal antibiotics can clear populations of S. aureus more effectively than the antibiotics alone.

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“…For more considerations of the role of population dynamic processes for the therapeutic use of phages, see ref. 47 .…”

Section: Discussionmentioning

confidence: 99%

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

Berryhill

Huseby

McCall

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“… 2016 ) and the resurrection of interest in phage therapy (Forti et al . 2018 ; Bull, Levin, and Molineux 2019 ; Cafora et al . 2019 ; Schmidt 2019 ), this question—and more broadly, studies of the population and evolutionary dynamics of the interactions between bacteria and phage—have become an increasingly important and relevant avenue of research.…”

Section: Introductionmentioning

confidence: 99%

Mucoidy, a general mechanism for maintaining lytic phage in populations of bacteria

Chaudhry

Lee

Worthy

et al. 2020

FEMS Microbiology Ecology

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We present evidence that phage resistance resulting from overproduction of exopolysaccharides, mucoidy, provides a general answer to the longstanding question of how lytic viruses are maintained in populations dominated by bacteria upon which they cannot replicate. In serial transfer culture, populations of mucoid E. coli MG1655 that are resistant to lytic phages with different receptors, and thereby requiring independent mutations for surface resistance, are capable of maintaining these phages with little effect on their total density. Based on the results of our analysis of a mathematical model, we postulate that the maintenance of phage in populations dominated by mucoid cells can be attributed primarily to high rates of transition from the resistant mucoid states to susceptible non-mucoid states. Our tests with both population dynamic and single cell experiments as well as genomic analysis are consistent with this hypothesis. We discuss reasons for the generalized resistance of these mucoid E. coli, and the genetic and molecular mechanisms responsible for the high rate of transition from mucoid to sensitive states responsible for the maintenance of lytic phage in mucoid populations of E. coli.

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“…Two particularly promising therapeutic strategies that capitalize on within‐host evolution are to contain or eliminate micros using evolutionary trade‐offs and/or competitive effects (Table 1). [ 42,103–105 ] For instance, “phage steering” leverages trade‐offs through within‐host evolution to restore antibiotic sensitive genotypes (Box 2). Leveraging competitive effects has also shown promising results both in vitro [ 14,106 ] and in vivo.…”

Section: The Body As An Ecosystemmentioning

confidence: 99%

Fighting microbial pathogens by integrating host ecosystem interactions and evolution

et al. 2020

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Successful therapies to combat microbial diseases and cancers require incorporating ecological and evolutionary principles. Drawing upon the fields of ecology and evolutionary biology, we present a systems‐based approach in which host and disease‐causing factors are considered as part of a complex network of interactions, analogous to studies of “classical” ecosystems. Centering this approach around empirical examples of disease treatment, we present evidence that successful therapies invariably engage multiple interactions with other components of the host ecosystem. Many of these factors interact nonlinearly to yield synergistic benefits and curative outcomes. We argue that these synergies and nonlinear feedbacks must be leveraged to improve the study of pathogenesis in situ and to develop more effective therapies. An eco‐evolutionary systems perspective has surprising and important consequences, and we use it to articulate areas of high research priority for improving treatment strategies.

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Promises and pitfalls ofin vivoevolution to improve phage therapy

Cited by 7 publications

References 78 publications

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

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

Mucoidy, a general mechanism for maintaining lytic phage in populations of bacteria

Fighting microbial pathogens by integrating host ecosystem interactions and evolution

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