scholarly journals Phage Cocktail Development for Bacteriophage Therapy: Toward Improving Spectrum of Activity Breadth and Depth

2021 ◽  
Vol 14 (10) ◽  
pp. 1019
Author(s):  
Stephen T. Abedon ◽  
Katarzyna M. Danis-Wlodarczyk ◽  
Daniel J. Wozniak
Keyword(s):  
Antibacterial Agents ◽  
Phage Therapy ◽  
Cross Resistance ◽  
Phage Resistance ◽  
Bacterial Strains ◽  
Bacteriophage Therapy ◽  
Commercial Development ◽  
Phage Cocktail ◽  
Bacterial Mutation ◽  
Number Of Bacteria

Phage therapy is the use of bacterial viruses as antibacterial agents. A primary consideration for commercial development of phages for phage therapy is the number of different bacterial strains that are successfully targeted, as this defines the breadth of a phage cocktail’s spectrum of activity. Alternatively, phage cocktails may be used to reduce the potential for bacteria to evolve phage resistance. This, as we consider here, is in part a function of a cocktail’s ‘depth’ of activity. Improved cocktail depth is achieved through inclusion of at least two phages able to infect a single bacterial strain, especially two phages against which bacterial mutation to cross resistance is relatively rare. Here, we consider the breadth of activity of phage cocktails while taking both depth of activity and bacterial mutation to cross resistance into account. This is done by building on familiar algorithms normally used for determination solely of phage cocktail breadth of activity. We show in particular how phage cocktails for phage therapy may be rationally designed toward enhancing the number of bacteria impacted while also reducing the potential for a subset of those bacteria to evolve phage resistance, all as based on previously determined phage properties.

scholarly journals Phage Therapy with a focus on the Human Microbiota

Antibiotics ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 131 ◽  
Author(s):  
Ganeshan ◽  
Hosseinidoust
Keyword(s):  
Infectious Disease ◽  
Antibacterial Activity ◽  
Antibiotic Resistance ◽  
Therapeutic Agent ◽  
Phage Therapy ◽  
Arms Race ◽  
Phage Resistance ◽  
Bacteriophage Therapy ◽  
Human Gut ◽  
Human Microbiota

Bacteriophages are viruses that infect bacteria. After their discovery in the early 1900s, bacteriophages were a primary cure against infectious disease for almost 25 years, before being completely overshadowed by antibiotics. With the rise of antibiotic resistance, bacteriophages are being explored again for their antibacterial activity. One of the critical apprehensions regarding bacteriophage therapy, however, is the possibility of genome evolution, development of phage resistance, and subsequent perturbations to our microbiota. Through this review, we set out to explore the principles supporting the use of bacteriophages as a therapeutic agent, discuss the human gut microbiome in relation to the utilization of phage therapy, and the co-evolutionary arms race between host bacteria and phage in the context of the human microbiota.

scholarly journals Bacteriophage Therapy: An Alternative to Antibiotics—An Experimental Study in Mice

2019 ◽  
Vol 55 (03) ◽  
pp. 151-158
Author(s):  
Gopal Nath ◽  
Ram Janam ◽  
Rajesh Kumar ◽  
Mayank Gangwar
Keyword(s):  
Experimental Study ◽  
Pseudomonas Aeruginosa ◽  
Animal Model ◽  
Mortality Rate ◽  
Phage Therapy ◽  
Bacterial Challenge ◽  
Bacteriophage Therapy ◽  
Reduced Dose ◽  
Acute Infections ◽  
Phage Cocktail

AbstractThe present study was planned to evaluate the efficacy of Pseudomonas aeruginosa specific phages in immunocompromised septicemia animal model as an alternative to antibiotics. Five different sets of experiments were performed: prophylactic administration of phage cocktail (3 lytic and unique) before and simultaneous with bacterial challenge; and therapeutic, that is, administration of phage cocktail 6, 12, and 24 hours after the bacterial challenge. No mortality was observed when simultaneous and late administration of phages was done with respect to the bacterial challenge. Contrary to this, administration of phage cocktail 100 µL (1012 PFU/mL) of volume after 6 hours of the infection resulted in a mortality rate of 60%. However, no mortality could be observed with reduced dose of cocktail, that is, 108, 109, and 1010 PFU administered 6 hours after bacterial challenge. Phage therapy in acute infections initiated with very small dosage under strict supervision may give better results. However, further studies to determine the quantity and frequency of dosage of phage cocktail for septicemia of various durations is strongly indicated.

scholarly journals Prospects of using adaptive phagotherapy (Phage therapy) in the rehabilitation of post-Covid 19 patients (editorial).

2021 ◽  
Author(s):  
Natalia V Beloborodova ◽  
Andrey V. Grechko ◽  
Alexander Yu. Zurabov ◽  
Fedor M. Zurabov ◽  
Artem N. Kuzovlev ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Intensive Care ◽  
Phage Therapy ◽  
Rapid Development ◽  
Human Microbiome ◽  
Individual Case ◽  
Phage Resistance ◽  
Bacterial Strains ◽  
The World ◽  
Pure Lines

The work is devoted to the organization of postcovid rehabilitation by developing a strategy of adative phage therapy, which is the production and application of a complex of bacteriophages for a specific medical institution/department based on an up-to-date collection of hospital bacterial strains isolated from the biomaterial of patients of the same institution. Bacteriophages were actively used in the world in the 20-40s of the twentieth century in various fields of medicine, but the rapid development of phage resistance in each individual case limited their use. The use of complex preparations of bacteriophages from the collection pure lines of bacteriophages of the SPC "MikroMir" a set of various phages aimed at restoring the human microbiome after a covid infection allowed to sharply reduce the number of antibiotics used in intensive care units and reduce antibiotic resistance with proven safety of phage therapy.

scholarly journals Phage Resistance in Multidrug-Resistant Klebsiella pneumoniae ST258 Evolves via Diverse Mutations That Culminate in Impaired Adsorption

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Shayla Hesse ◽  
Manoj Rajaure ◽  
Erin Wall ◽  
Joy Johnson ◽  
Valery Bliskovsky ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Cell Surface ◽  
Phage Therapy ◽  
Surface Structures ◽  
Phage Resistance ◽  
Cell Surface Structures ◽  
Phage Cocktail ◽  
Resistant Mutants

ABSTRACT The evolution of phage resistance poses an inevitable threat to the efficacy of phage therapy. The strategic selection of phage combinations that impose high genetic barriers to resistance and/or high compensatory fitness costs may mitigate this threat. However, for such a strategy to be effective, the evolution of phage resistance must be sufficiently constrained to be consistent. In this study, we isolated lytic phages capable of infecting a modified Klebsiella pneumoniae clinical isolate and characterized a total of 57 phage-resistant mutants that evolved from their prolonged coculture in vitro. Single- and double-phage-resistant mutants were isolated from independently evolved replicate cocultures grown in broth or on plates. Among resistant isolates evolved against the same phage under the same conditions, mutations conferring resistance occurred in different genes, yet in each case, the putative functions of these genes clustered around the synthesis or assembly of specific cell surface structures. All resistant mutants demonstrated impaired phage adsorption, providing a strong indication that these cell surface structures functioned as phage receptors. Combinations of phages targeting different host receptors reduced the incidence of resistance, while, conversely, one three-phage cocktail containing two phages targeting the same receptor increased the incidence of resistance (relative to its two-phage, nonredundant receptor-targeting counterpart). Together, these data suggest that laboratory characterization of phage-resistant mutants is a useful tool to help optimize therapeutic phage selection and cocktail design. IMPORTANCE The therapeutic use of bacteriophage (phage) is garnering renewed interest in the setting of difficult-to-treat infections. Phage resistance is one major limitation of phage therapy; therefore, developing effective strategies to avert or lessen its impact is critical. Characterization of in vitro phage resistance may be an important first step in evaluating the relative likelihood with which phage-resistant populations emerge, the most likely phenotypes of resistant mutants, and the effect of certain phage cocktail combinations in increasing or decreasing the genetic barrier to resistance. If this information confers predictive power in vivo, then routine studies of phage-resistant mutants and their in vitro evolution should be a valuable means for improving the safety and efficacy of phage therapy in humans.

scholarly journals Wzc and WcaJ mutations in hypervirulent Klebsiella pneumoniae lead to phage resistance at the cost of reduced virulence

2021 ◽  
Author(s):  
Lingjie Song ◽  
Xianggui Yang ◽  
Jinwei Huang ◽  
Xiaokui Zhu ◽  
Guohui Han ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Phage Therapy ◽  
Genomic Analysis ◽  
Resistant Bacteria ◽  
Phage Resistance ◽  
Comparative Genomic ◽  
Sequencing Analysis ◽  
Bacteriophage Therapy ◽  
Invasive Infections ◽  
The Cost

AbstractHypervirulent Klebsiella pneumoniae (hvKp) is one of the major community-acquired pathogens, which can cause invasive infections such as liver abscess. In recent years, bacteriophages have been used in the treatment of Klebsiella pneumoniae, but the characteristics of the phage resistant bacteria produced in the process of phage therapy need to be evaluated. In this study, two podoviridae phages, hvKpP1 and hvKpP2, were isolated and characterized. In vitro and in vivo experiments demonstrated that the virulence of the resistant bacteria was significantly reduced compared with that of the wild type. Comparative genomic analysis of monoclonal sequencing showed that nucleotide deletion mutations of wzc and wcaJ genes led to phage resistance, and the electron microscopy and mucoviscosity results showed that mutations led to the loss of the capsule, meanwhile, animal assay indicated that loss of capsule reduced the virulence of hvKp. The findings can contribute to a better understanding of that bacteriophage therapy can not only kill bacteria directly, but also reduce the virulence of bacteria by phage screening.ImportanceBacteriophages are considered potential therapeutic alternative to antibiotics; however host-evolved phage resistance has accounted for the resurgences of pathogens, meaning further measures are need to improve the efficacy of phage therapy. This study showed two phages capable of infecting hypervirulent K. pneumoniae and identified phage-resistant mutants whose virulence was significantly reduced. Gene sequencing analysis revealed that mutations of wzc and wcaJ gene, related to capsule synthesis, recovered phage resistance but reduced the virulence of hypervirulent K. pneumoniae.

scholarly journals Transposon Insertion Sequencing Elucidates Novel Gene Involvement in Susceptibility and Resistance to Phages T4 and T7 inEscherichia coliO157

mBio ◽  
2018 ◽  
Vol 9 (4) ◽  
Author(s):  
Lauren A. Cowley ◽  
Alison S. Low ◽  
Derek Pickard ◽  
Christine J. Boinett ◽  
Timothy J. Dallman ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Bacterial Infections ◽  
Phage Therapy ◽  
Phage Infection ◽  
Phage Typing ◽  
Phage Resistance ◽  
Bacterial Strains ◽  
Content Type ◽  
Successful Infection ◽  
Susceptibility And Resistance

ABSTRACTExperiments using bacteriophage (phage) to infect bacterial strains have helped define some basic genetic concepts in microbiology, but our understanding of the complexity of bacterium-phage interactions is still limited. As the global threat of antibiotic resistance continues to increase, phage therapy has reemerged as an attractive alternative or supplement to treating antibiotic-resistant bacterial infections. Further, the long-used method of phage typing to classify bacterial strains is being replaced by molecular genetic techniques. Thus, there is a growing need for a complete understanding of the precise molecular mechanisms underpinning phage-bacterium interactions to optimize phage therapy for the clinic as well as for retrospectively interpreting phage typing data on the molecular level. In this study, a genomics-based fitness assay (TraDIS) was used to identify all host genes involved in phage susceptibility and resistance for a T4 phage infecting Shiga-toxigenicEscherichia coliO157. The TraDIS results identified both established and previously unidentified genes involved in phage infection, and a subset were confirmed by site-directed mutagenesis and phenotypic testing of 14 T4 and 2 T7 phages. For the first time, the entiresapoperon was implicated in phage susceptibility and, conversely, the stringent starvation protein A gene (sspA) was shown to provide phage resistance. Identifying genes involved in phage infection and replication should facilitate the selection of bespoke phage combinations to target specific bacterial pathogens.IMPORTANCEAntibiotic resistance has diminished treatment options for many common bacterial infections. Phage therapy is an alternative option that was once popularly used across Europe to kill bacteria within humans. Phage therapy acts by using highly specific viruses (called phages) that infect and lyse certain bacterial species to treat the infection. Whole-genome sequencing has allowed modernization of the investigations into phage-bacterium interactions. Here, usingE. coliO157 and T4 bacteriophage as a model, we have exploited a genome-wide fitness assay to investigate all genes involved in defining phage resistance or susceptibility. This knowledge of the genetic determinants of phage resistance and susceptibility can be used to design bespoke phage combinations targeted to specific bacterial infections for successful infection eradication.

scholarly journals Beehive Products as Antibacterial Agents: A Review

Antibiotics ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 717
Author(s):  
Rita Abou Nader ◽  
Rawan Mackieh ◽  
Rim Wehbe ◽  
Dany El El Obeid ◽  
Jean Marc Sabatier ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Honey Bee ◽  
Antibacterial Agents ◽  
Royal Jelly ◽  
Biological Activities ◽  
Vital Role ◽  
Bee Venom ◽  
Bacterial Strains ◽  
Wide Range ◽  
Life Threatening

Honeybees are one of the most marvelous and economically beneficial insects. As pollinators, they play a vital role in every aspect of the ecosystem. Beehive products have been used for thousands of years in many cultures for the treatment of various diseases. Their healing properties have been documented in many religious texts like the Noble Quran and the Holy Bible. Honey, bee venom, propolis, pollen and royal jelly all demonstrated a richness in their bioactive compounds which make them effective against a variety of bacterial strains. Furthermore, many studies showed that honey and bee venom work as powerful antibacterial agents against a wide range of bacteria including life-threatening bacteria. Several reports documented the biological activities of honeybee products but none of them emphasized on the antibacterial activity of all beehive products. Therefore, this review aims to highlight the antibacterial activity of honey, bee venom, propolis, pollen and royal jelly, that are produced by honeybees.

scholarly journals Exploring Mucin as Adjunct to Phage Therapy

2021 ◽  
Vol 9 (3) ◽  
pp. 509
Author(s):  
Amanda Carroll-Portillo ◽  
Henry C. Lin
Keyword(s):  
Pathogenic Bacteria ◽  
Structural Changes ◽  
Phage Therapy ◽  
Bacterial Species ◽  
Gi Tract ◽  
Beneficial Bacteria ◽  
Phage Cocktail ◽  
Small Intestinal ◽  
Gastrointestinal Dysbiosis

Conventional phage therapy using bacteriophages (phages) for specific targeting of pathogenic bacteria is not always useful as a therapeutic for gastrointestinal (GI) dysfunction. Complex dysbiotic GI disorders such as small intestinal bowel overgrowth (SIBO), ulcerative colitis (UC), or Crohn’s disease (CD) are even more difficult to treat as these conditions have shifts in multiple populations of bacteria within the microbiome. Such community-level structural changes in the gut microbiota may require an alternative to conventional phage therapy such as fecal virome transfer or a phage cocktail capable of targeting multiple bacterial species. Additionally, manipulation of the GI microenvironment may enhance beneficial bacteria–phage interactions during treatment. Mucin, produced along the entire length of the GI tract to protect the underlying mucosa, is a prominent contributor to the GI microenvironment and may facilitate bacteria–phage interactions in multiple ways, potentially serving as an adjunct during phage therapy. In this review, we will describe what is known about the role of mucin within the GI tract and how its facilitation of bacteria–phage interactions should be considered in any effort directed at optimizing effectiveness of a phage therapy for gastrointestinal dysbiosis.

scholarly journals Assessment of the microbiome during bacteriophage therapy in combination with systemic antibiotics to treat a case of staphylococcal device infection

Microbiome ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Andre Mu ◽  
Daniel McDonald ◽  
Alan K. Jarmusch ◽  
Cameron Martino ◽  
Caitriona Brennan ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Phage Therapy ◽  
Ecological Impacts ◽  
Skin Microbiome ◽  
Bacteriophage Therapy ◽  
Bacterial Diseases ◽  
Device Infection ◽  
Global Health Issue ◽  
Serious Bacterial Infections ◽  
Systemic Antibiotics

Abstract Background Infectious bacterial diseases exhibiting increasing resistance to antibiotics are a serious global health issue. Bacteriophage therapy is an anti-microbial alternative to treat patients with serious bacterial infections. However, the impacts to the host microbiome in response to clinical use of phage therapy are not well understood. Results Our paper demonstrates a largely unchanged microbiota profile during 4 weeks of phage therapy when added to systemic antibiotics in a single patient with Staphylococcus aureus device infection. Metabolomic analyses suggest potential indirect cascading ecological impacts to the host (skin) microbiome. We did not detect genomes of the three phages used to treat the patient in metagenomic samples taken from saliva, stool, and skin; however, phages were detected using endpoint-PCR in patient serum. Conclusion Results from our proof-of-principal study supports the use of bacteriophages as a microbiome-sparing approach to treat bacterial infections.

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