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All sourcesNASA NTRSDOE OSTI
DOE OSTI2020

Current challenges and future opportunities of phage therapy

ABSTRACT Antibiotic resistance is a major public health challenge worldwide, whose implications for global health might be devastating if novel antibacterial strategies are not quickly developed. As natural predators of bacteria, (bacterio)phages may play an essential role in escaping such a dreadful future. The rising problem of antibiotic resistance has revived the interest in phage therapy and important developments have been achieved over the last years. But where do we stand today and what can we expect from phage therapy in the future? This is the question we set to answer in this review. Here, we scour the outcomes of human phage therapy clinical trials and case reports, and address the major barriers that stand in the way of using phages in clinical settings. We particularly address the potential of phage resistance to hinder phage therapy and discuss future avenues to explore the full capacity of phage therapy.

Pires, Diana P.↗
DOE OSTI2026

Towards modeling phage therapy

Patients infected with life-threatening multi-drug resistant (MDR) bacteria have been treated with cocktails of bacteriophages. This is a complicated form of personalized medicine as the phages given to a patient have to be selected beforehand on the basis of their lytic capacity of the infecting bacteria. Because bacteria rapidly become resistant, the evolution of resistance to a diverse cocktail of phages is a complicated dynamical process, during which competing bacterial strains replace one another by accumulating several resistance mechanisms, each of which may involve a fitness cost. As a consequence, it is typically not known why a particular phage therapy succeeded or failed, and how one can optimize the composition of the cocktails to maximize the rate of success. To improve upon this, we extend an existing in vivo -calibrated mouse model into a novel mathematical model for the human situation, and include multiple phages infecting multiple bacterial strains, differing in their resistance to each of the phages. We adjust several parameter estimates of the bacterial model to the human situation, and use the model to describe a successful case of phage therapy involving several cocktails, each containing several phages. In the model, treatment success crucially depended on pretreatment resistance levels, and on the diversity and the timing of the cocktails. Once an appropriate cocktail is found, it is less important to further optimize the infection rates of the phages. Resistant bacterial strains expand rapidly when sensitive strains decline, and the higher the infectivity of the phages, the faster resistant strains expand. Because resistance evolves rapidly, it is best to provide a diverse set of phages right from the start of therapy, i.e., to hit hard and early, and create a high genetic barrier to bacterial resistance.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Phage therapy: From biological mechanisms to future directions

Increasing antimicrobial resistance rates have revitalized bacteriophage (phage) research, the natural predators of bacteria discovered over 100 years ago. In order to use phages therapeutically, they should (1) preferably be lytic, (2) kill the bacterial host efficiently, and (3) be fully characterized to exclude side effects. Developing therapeutic phages takes a coordinated effort of multiple stakeholders. Herein, we review the state of the art in phage therapy, covering biological mechanisms, clinical applications, remaining challenges, and future directions involving naturally occurring and genetically modified or synthetic phages.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Enabling generalized phage therapy to treat secondary infections in COVID-19 (CRADA Final Report)

COVID-19 is a global health threat, with 32 millions infected and more than 500,000 deaths in the U.S. alone. A key aspect of COVID-19 deaths is bacterial secondary infections, with Staphylococcus aureus, Acinetobacter baumannii, and Pseudomonas aeruginosa identified as some of the major causative pathogens. Phage therapy, i.e., the administration of bacteriophages (viruses infecting these bacterial pathogens) to patients offers a complementary solution to antibiotics with multiple key advantages. Felix Biotechnology’s is developing a high-throughput platform to identify phages that not only kill pathogens, but also drive targeted trade-off of pathogenic phenotypes such as reduced virulence and antibiotic resistance, at a fraction of the time and R&D cost of any competitor. In this project, collaboration with scientists from the Lawrence Berkeley National Laboratory enabled Felix Biotechnology to establish robust analysis pipeline to investigate phage-host interactions in complex samples. These should enable a quick and robust identification of promising phages and key genetic determinants for therapy applications, paving the way towards a streamlined and safe use of phages in the clinic.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Lessons from bacteriophages part 2: A saga of scientific breakthroughs and prospects for their use in human health

Bacteriophages, or phages, are considered the most abundant entities on the planet, with their total numbers ranging from 10 30 ± 10 31 particles. Phages are known to play an important role in driving the evolution of their bacterial hosts, mostly via generalized and specialized transduction mechanisms. Phage therapy as a means to eliminate bacterial pathogens was used first in the 1920s; however, its use declined due to the advent of antibiotics in the 1940s. Eastern European countries have performed human trials for phage therapy for a century now, including a phage therapy trial in 1938 at the Eliava Institute of Bacteriophage in Georgia that successfully eliminated bacterial dysentery in 74% of the 219 cases by using a phage cocktail that targeted a wide range of causative agents for dysentery. Here, we present some of the major contributions of phage research to human health.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Diversified Therapeutic Phage Cocktails from Close Relatives of the Target Bacterium

This project tackles the antibiotic resistance crisis, developing a new method for discovering numerous efficacious bacteriophages for therapeutic cocktails against bacterial pathogens. The phage therapy approach to infectious disease, recently rekindled in U.S. medicine, requires numerous phages for each bacterial pathogen. Our approach 1) uses Sandia-unique software to identify dormant phages (prophages) integrated into bacterial chromosomes, 2) identifies prophage-laden bacteria that are close relatives of the target pathogenic strain to be killed, and 3) engineers away properties of these phages that are undesirable for therapy. We have perfected our phage-finding software, implemented our phage therapy strategy by targeting the pathogen Pseudomonas aeruginosa, and prepared new software to assist the phage engineering. We then turned toward Burkholderia pathogens, aiming to overcome the difficulty to transform these bacteria with a novel phage conjugation approach. Our work demonstrates the validity of a new approach to phage therapy for killing antibiotic resistant pathogens.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2012

Structural engineering of a phage lysin that targets Gram-negative pathogens

Bacterial pathogens are becoming increasingly resistant to antibiotics. As an alternative therapeutic strategy, phage therapy reagents containing purified viral lysins have been developed against Gram-positive organisms but not against Gram-negative organisms due to the inability of these types of drugs to cross the bacterial outer membrane. We solved the crystal structures of a Yersinia pestis outer membrane transporter called FyuA and a bacterial toxin called pesticin that targets this transporter. FyuA is a {beta}-barrel membrane protein belonging to the family of TonB dependent transporters, whereas pesticin is a soluble protein with two domains, one that binds to FyuA and another that is structurally similar to phage T4 lysozyme. The structure of pesticin allowed us to design a phage therapy reagent comprised of the FyuA binding domain of pesticin fused to the N-terminus of T4 lysozyme. This hybrid toxin kills specific Yersinia and pathogenic E. coli strains and, importantly, can evade the pesticin immunity protein (Pim) giving it a distinct advantage over pesticin. Furthermore, because FyuA is required for virulence and is more common in pathogenic bacteria, the hybrid toxin also has the advantage of targeting primarily disease-causing bacteria rather than indiscriminately eliminating natural gut flora.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Virion glycosylation influences mycobacteriophage immune recognition

Glycosylation of eukaryotic virus particles is common and influences their uptake, trafficking, and immune recognition. In contrast, glycosylation of bacteriophage particles has not been reported; phage virions typically do not enter the cytoplasm upon infection, and they do not generally inhabit eukaryotic systems. We show here that several genomically distinct phages of Mycobacteria are modified with glycans attached to the C terminus of capsid and tail tube protein subunits. These O-linked glycans influence antibody production and recognition, shielding viral particles from antibody binding and reducing production of neutralizing antibodies. Glycosylation is mediated by phage-encoded glycosyltransferases, and genomic analysis suggests that they are relatively common among mycobacteriophages. Putative glycosyltransferases are also encoded by some Gordonia and Streptomyces phages, but there is little evidence of glycosylation among the broader phage population. The immune response to glycosylated phage virions in mice suggests that glycosylation may be an advantageous property for phage therapy of Mycobacterium infections.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

A Phage Foundry Framework to Systematically Develop Viral Countermeasures to Combat Antibiotic-Resistant Bacterial Pathogens

At its current rate, the rise of antimicrobial-resistant (AMR) infections is predicted to paralyze our industries and healthcare facilities while becoming the leading global cause of loss of human life. With limited new antibiotics on the horizon, we need to invest in alternative solutions. Bacteriophages (phages)–viruses targeting bacteria–offer a powerful alternative approach to tackle bacterial infections. Despite recent advances in using phages to treat recalcitrant AMR infections, the field lacks systematic development of phage therapies scalable to different applications. We propose a Phage Foundry framework to establish metrics for phage characterization and to fill the knowledge and technological gaps in phage therapeutics. Coordinated investment in AMR surveillance, sampling, characterization, and data sharing procedures will enable rational exploitation of phages for treatments. A fully realized Phage Foundry will enhance the sharing of knowledge, technology, and viral reagents in an equitable manner and will accelerate the biobased economy.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

The clinical path to deliver encapsulated phages and lysins

ABSTRACT The global emergence of multidrug-resistant pathogens is shaping the current dogma regarding the use of antibiotherapy. Many bacteria have evolved to become resistant to conventional antibiotherapy, representing a health and economic burden for those afflicted. The search for alternative and complementary therapeutic approaches has intensified and revived phage therapy. In recent decades, the exogenous use of lysins, encoded in phage genomes, has shown encouraging effectiveness. These two antimicrobial agents reduce bacterial populations; however, many barriers challenge their prompt delivery at the infection site. Encapsulation in delivery vehicles provides targeted therapy with a controlled compound delivery, surpassing chemical, physical and immunological barriers that can inactivate and eliminate them. This review explores phages and lysins' current use to resolve bacterial infections in the respiratory, digestive and integumentary systems. We also highlight the different challenges they face in each of the three systems and discuss the advances towards a more expansive use of delivery vehicles.

Pinto, Ana Mafalda↗
DOE OSTI2012

PHACTS, a computational approach to classifying the lifestyle of phages

Motivation: Bacteriophages have two distinct lifestyles: virulent and temperate. The virulent lifestyle has many implications for phage therapy, genomics and microbiology. Determining which lifestyle a newly sequenced phage falls into is currently determined using standard culturing techniques. Such laboratory work is not only costly and time consuming, but also cannot be used on phage genomes constructed from environmental sequencing. Therefore, a computational method that utilizes the sequence data of phage genomes is needed. Results: Phage Classification Tool Set (PHACTS) utilizes a novel similarity algorithm and a supervised Random Forest classifier to make a prediction whether the lifestyle of a phage, described by its proteome, is virulent or temperate. The similarity algorithm creates a training set from phages with known lifestyles and along with the lifestyle annotation, trains a Random Forest to classify the lifestyle of a phage. PHACTS predictions are shown to have a 99% precision rate.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2013

Safety analysis of a Russian phage cocktail: From MetaGenomic analysis to oral application in healthy human subjects

Phage therapy has a long tradition in Eastern Europe, where preparations are comprised of complex phage cocktails whose compositions have not been described. We investigated the composition of a phage cocktail from the Russian pharmaceutical company Microgen targeting Escherichia coli/Proteus infections. Electron microscopy identified six phage types, with numerically T7-like phages dominating over T4-like phages. A metagenomic approach using taxonomical classification, reference mapping and de novo assembly identified 18 distinct phage types, including 7 genera of Podoviridae, 2 established and 2 proposed genera of Myoviridae, and 2 genera of Siphoviridae. De novo assembly yielded 7 contigs greater than 30 kb, including a 147-kb Myovirus genome and a 42-kb genome of a potentially new phage. Bioinformatic analysis did not reveal undesired genes and a small human volunteer trial did not associate adverse effects with oral phage exposure. - Highlights: • We analyzed the composition of a commercial Russian phage cocktail. • The cocktail consists of at least 10 different phage genera. • No undesired genes were detected. • No adverse effects were seen upon oral application in a small human clinical trial.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Mycobacterium Phage Butters-Encoded Proteins Contribute to Host Defense against Viral Attack [plus supplemental information]

A diverse set of prophage-mediated mechanisms protecting bacterial hosts from infection has been recently uncovered within cluster N mycobacteriophages isolated on the host, Mycobacterium smegmatis mc 2 155. In that context, we unveil a novel defense mechanism in cluster N prophage Butters. By using bioinformatics analyses, phage plating efficiency experiments, microscopy, and immunoprecipitation assays, we show that Butters genes located in the central region of the genome play a key role in the defense against heterotypic viral attack. Our study suggests that a two-component system, articulated by interactions between protein products of genes 30 and 31, confers defense against heterotypic phage infection by PurpleHaze (cluster A/subcluster A3) or Alma (cluster A/subcluster A9) but is insufficient to confer defense against attack by the heterotypic phage Island3 (cluster I/subcluster I1). Therefore, based on heterotypic phage plating efficiencies on the Butters lysogen, additional prophage genes required for defense are implicated and further show specificity of prophage-encoded defense systems. IMPORTANCE: Many sequenced bacterial genomes, including those of pathogenic bacteria, contain prophages. Some prophages encode defense systems that protect their bacterial host against heterotypic viral attack. Understanding the mechanisms undergirding these defense systems is crucial to appreciate the scope of bacterial immunity against viral infections and will be critical for better implementation of phage therapy that would require evasion of these defenses. Furthermore, such knowledge of prophage-encoded defense mechanisms may be useful for developing novel genetic tools for engineering phage-resistant bacteria of industrial importance.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Exploring phage–host interactions in Burkholderia cepacia complex bacterium to reveal host factors and phage resistance genes using CRISPRi functional genomics and transcriptomics

Complex interactions of bacteriophages with their bacterial hosts determine phage host range and infectivity. While phage defense systems and host factors have been identified in model bacteria, they remain challenging to predict in non-model bacteria. In this paper, we integrate functional genomics and transcriptomics to investigate phage–host interactions, revealing active phage resistance and host factor genes in Burkholderia cenocepacia K56-2. Burkholderia cepacia complex species are commonly found in soil and are opportunistic pathogens in immunocompromised patients. We studied infection of B. cenocepacia K56-2 with Bcep176, a temperate phage isolated from Burkholderia multivorans. A genome-wide dCas9 knockdown library targeting B. cenocepacia K56-2 was constructed, and a pooled infection experiment identified 63 novel genes or operons coding for candidate host factors or phage resistance genes. The activities of a subset of candidate host factor and resistance genes were validated via single-gene knockdowns. Transcriptomics of B. cenocepacia K56-2 during Bcep176 infection revealed that expression of genes coding for host factor and resistance candidates identified in this screen was significantly altered during infection by 4 h post-infection. Identifying which bacterial genes are involved in phage infection is important to understand the ecological niches of B. cenocepacia and its phages, and for designing phage therapies.

Bacterial Pathogenesis↗