Phage Therapy in the Twenty-First Century: Facing the Decline of the Antibiotic Era; Is It Finally Time for the Age of the Phage?

Hesse, Shayla; Adhya, Sankar

doi:10.1146/annurev-micro-090817-062535

Cited by 87 publications

(57 citation statements)

References 88 publications

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“…The adaptability and sheer number of phages imply that they are the largest repository of antibacterial information available to modern medicine. Furthermore, phages have been used to treat bacterial infections for decades in Eastern Europe, and recent compassionate care cases in the U.S. and U.K. has demonstrated clinical success (9,10). Phages are also specific for a given bacterial species (even strain), meaning off-target killing of "good" bacteria in our microbiome can be minimized.…”

Section: Five Years Later In 2019 the Centers For Disease Control Anmentioning

confidence: 99%

Phage-Antibiotic Synergy is Driven by a Unique Combination of Antibacterial Mechanism of Action and Stoichiometry

Liu

Green

Min

et al. 2020

Preprint

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The continued rise in antibiotic resistance is precipitating a medical crisis. Bacteriophage (phage) has been hailed as one possible therapeutic option to augment the efficacy of antibiotics.However, only a handful of studies have addressed the synergistic relationship between phage and antibiotics. Here, we report a comprehensive analysis of phage-antibiotic interaction that evaluates synergism, additivism, and antagonism for all classes of antibiotics across clinically achievable stoichiometries. We combined an optically-based real-time microtiter plate readout with a matrix-like heatmap of treatment potencies to measure phage and antibiotic synergy (PAS), a process we term synography. Phage-antibiotic synography was performed against a pandemic drug-resistant clonal group of E. coli (ExPEC) with antibiotic levels blanketing the minimum inhibitor concentration (MIC) across seven orders of viral titers. Our results suggest that, under certain conditions, phages provide an adjuvating effect by lowering the MIC for drugresistant strains. Furthermore, synergistic and antagonistic interactions are highly dependent on the mechanism of bacterial inhibition by the class of antibiotic paired to the phage, and when synergism is observed, it suppresses the emergence of resistant cells. Host conditions that simulate the infection environment, including serum and urine, suppress PAS in a bacterial growth-dependent manner. Lastly, phage burst size seems to be a significant driver of synergism.Collectively, this data suggests lytic phages can resuscitate an ineffective antibiotic for previously resistant bacteria, while also synergize with antibiotics in a class-dependent manner, processes that may be dampened by lower bacterial growth rates found in host environments. Significance StatementBacteriophage (phage) therapy is a promising approach to combat the rise of multi-drug resistant bacteria. Currently, the preferred clinical modality is to pair phage with an antibiotic, a practice thought to improve efficacy. However, antagonism between phage and antibiotics has been reported, the choice of phage and antibiotic is not often empirically determined, and the effect of the host factors on the effectiveness is unknown. Here, we interrogate phage-antibiotic interactions across antibiotics with different mechanisms of action. Our results suggest that phage can lower the working MIC for bacterial strains already resistant to the antibiotic, is dependent on the antibiotic class and stoichiometry of the pairing, and is dramatically influenced by the host microenvironment.

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Section: Five Years Later In 2019 the Centers For Disease Control Anmentioning

confidence: 99%

Phage-Antibiotic Synergy is Driven by a Unique Combination of Antibacterial Mechanism of Action and Stoichiometry

Liu

Green

Min

et al. 2020

Preprint

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“…An interesting approach uses phages to deliver CRISPR-Cas cassettes as antimicrobials (6,7), although this strategy faces challenges with efficient delivery to a wider range of bacterial targets (8). In addition, the pharmacokinetics and pharmacodynamics of phages are difficult to model due to their exponential replication, presenting a major barrier to clinical translation (9). Exponential replication may also lead to undesirably rapid release of bacterial endotoxins (10).…”

mentioning

confidence: 99%

Controlled phage therapy by photothermal ablation of specific bacterial species using gold nanorods targeted by chimeric phages

Peng

Borg

Dow

et al. 2020

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

109

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The use of bacteriophages (phages) for antibacterial therapy is under increasing consideration to treat antimicrobial-resistant infections. Phages have evolved multiple mechanisms to target their bacterial hosts, such as high-affinity, environmentally hardy receptor-binding proteins. However, traditional phage therapy suffers from multiple challenges stemming from the use of an exponentially replicating, evolving entity whose biology is not fully characterized (e.g., potential gene transduction). To address this problem, we conjugate the phages to gold nanorods, creating a reagent that can be destroyed upon use (termed “phanorods”). Chimeric phages were engineered to attach specifically to several Gram-negative organisms, including the human pathogens Escherichia coli, Pseudomonas aeruginosa, and Vibrio cholerae, and the plant pathogen Xanthomonas campestris. The bioconjugated phanorods could selectively target and kill specific bacterial cells using photothermal ablation. Following excitation by near-infrared light, gold nanorods release energy through nonradiative decay pathways, locally generating heat that efficiently kills targeted bacterial cells. Specificity was highlighted in the context of a P. aeruginosa biofilm, in which phanorod irradiation killed bacterial cells while causing minimal damage to epithelial cells. Local temperature and viscosity measurements revealed highly localized and selective ablation of the bacteria. Irradiation of the phanorods also destroyed the phages, preventing replication and reducing potential risks of traditional phage therapy while enabling control over dosing. The phanorod strategy integrates the highly evolved targeting strategies of phages with the photothermal properties of gold nanorods, creating a well-controlled platform for systematic killing of bacterial cells.

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“…Examples include colicins that are known for their narrow killing spectrum (Cascales et al, 2007), recently developed fimbriae antagonists against some pathogenic strains of Escherichia coli (Spaulding et al, 2017), and several species-specific antibodies (Cattoir & Felden, 2019). Phages are highly specific for their bacterial targets, and are resurfacing as an attractive treatment option in refractory bacterial infections thanks to their activity against antibiotic-resistant pathogens and a lack of serious side effects (Hesse & Adhya, 2019). The renewed interest in phage therapy coincides with advances in our understanding of antiphage defense systems such as CRISPR-Cas which themselves, when repurposed as an antibacterial weapon (Beisel, Gomaa, & Barrangou, 2014;Bikard et al, 2014;Citorik, Mimee, & Lu, 2014), represent another strong alternative to broad-spectrum antibiotics.…”

Section: Vogelmentioning

confidence: 99%

An RNA biology perspective on species‐specific programmable RNA antibiotics

Vogel

2020

Molecular Microbiology

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Our body is colonized by a vast array of bacteria the sum of which forms our microbiota. The gut alone harbors >1,000 bacterial species. An understanding of their individual or synergistic contributions to human health and disease demands means to interfere with their functions on the species level. Most of the currently available antibiotics are broad‐spectrum, thus too unspecific for a selective depletion of a single species of interest from the microbiota. Programmable RNA antibiotics in the form of short antisense oligonucleotides (ASOs) promise to achieve precision manipulation of bacterial communities. These ASOs are coupled to small peptides that carry them inside the bacteria to silence mRNAs of essential genes, for example, to target antibiotic‐resistant pathogens as an alternative to standard antibiotics. There is already proof‐of‐principle with diverse bacteria, but many open questions remain with respect to true species specificity, potential off‐targeting, choice of peptides for delivery, bacterial resistance mechanisms and the host response. While there is unlikely a one‐fits‐all solution for all microbiome species, I will discuss how recent progress in bacterial RNA biology may help to accelerate the development of programmable RNA antibiotics for microbiome editing and other applications.

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Phage Therapy in the Twenty-First Century: Facing the Decline of the Antibiotic Era; Is It Finally Time for the Age of the Phage?

Cited by 87 publications

References 88 publications

Phage-Antibiotic Synergy is Driven by a Unique Combination of Antibacterial Mechanism of Action and Stoichiometry

Phage-Antibiotic Synergy is Driven by a Unique Combination of Antibacterial Mechanism of Action and Stoichiometry

Controlled phage therapy by photothermal ablation of specific bacterial species using gold nanorods targeted by chimeric phages

An RNA biology perspective on species‐specific programmable RNA antibiotics

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