Bacteriophage therapy- a refurbished age-old potential strategy to treat antibiotic and multidrug resistant bacterial infections in future.

The worldwide prevalence of antimicrobial resistance coupled with the unavailability of newer antibiotics, has brought the sharp focus back among the scientific community, towards the discovery of novel alternative therapeutics to tackle the menace. Consequently, in the current post-antibiotic era, 'Bacteriophage Therapy' has emerged as one of the most promising option to address this problem. Bacteriophages, actually discovered long back, has shown greater potential to kill various bacterial pathogens, including the resistant clinical ones. Some of the other advantages for the use of bacteriophage therapy to treat infectious diseases include, wider availability of these microorganisms in nature, host-specific action, absence of any significant side-effects in humans and most often also exhibiting a broader anti-bacterial potential. In the recent times, the potential of phage therapy has been demonstrated in various treatments, clinical trials and infection models across the globe, where even antibiotics have completely failed. To address the global threat of AMR, WHO and UN have jointly illustrated "One Health" approach, recently extending the context to bacteriophage therapy. Many pharmaceutical companies have also recently started employing bacteriophages for developing different kinds of formulations for catering to medical and other industries. It has even shown great effect as combinatorial therapy along with antibiotics, to treat or manage various critical antibiotic resistant clinical infections. This continuously expanding potential of the bacteriophages holds great promise in the future, in the fight against the rising threat of AMR globally.

Implications of lytic phage infections inducing persistence.

Phage therapy holds much promise as an alternative to antibiotics for fighting infection. However, this approach is no panacea as recent results show that a small fraction of cells survives lytic phage infection due to both dormancy (i.e. formation of persister cells) and resistance (genetic change). In this brief review, we summarize evidence suggesting phages induce the persister state. Therefore, it is predicted that phage cocktails should be combined with antipersister compounds to eradicate bacterial infections.

Actualización en fibrosis quística - fagoterapia: ¿es el futuro para tratar bacterias multirresistentes? / Phage therapy: is the future to treat multiresistant bacteria?

Las infecciones respiratorias representan una morbilidad y mortalidad significativas, con aumento progresivo de la resistencia a los antibióticos. La escasez de nuevos antibióticos disponibles y la pérdida de eficacia de los antiguos, ha impulsado a investigar otras alternativas de tratamiento. La terapia con bacteriófagos (fagos) representa uno de esos enfoques, la que ha demostrado ser eficaz contra una variedad de patógenos bacterianos, incluidas las cepas resistentes a los medicamentos. La administración puede ser tópica, intravenosa o inhalada, esta última requiere preparaciones estables de fagos y sistemas adecuados para proporcionar partículas que accedan al árbol respiratorio. En esta comunicación se revisan diversos aspectos de los bacteriófagos, los que podrían ser de gran utilidad para el tratamiento de las infecciones pulmonares en pacientes con diagnóstico de fibrosis quística.

Respiratory infections represent a significant morbidity and mortality, with a progressive increase in resistance to antibiotics. The scarcity of new antibiotics available and the loss of efficacy of the old ones has prompted investigation of other treatment alternatives. Bacteriophage (phage) therapy represents one such approach that has been shown to be effective against a variety of bacterial pathogens, including resistant strains to medications. Administration can be topical. Intravenous or inhaled, the latter requiring stable preparations of phages and adequate systems to provide particles that will access the respiratory tree. In this communication various aspects of bacteriophages and their clinical utility are reviewed, which could be very useful for the treatment of pulmonary infections in patients diagnosed with cystic fibrosis.

Efficacy of Salmonella Bacteriophage S1 Delivered and Released by Alginate Beads in a Chicken Model of Infection.

Modern bacteriophage encapsulation methods based on polymers such as alginate have been developed recently for their use in phage therapy for veterinary purposes. In birds, it has been proven that using this delivery system allows the release of the bacteriophage in the small intestine, the site of infection by Salmonella spp. This work designed an approach for phage therapy using encapsulation by ionotropic gelation of the lytic bacteriophage S1 for Salmonella enterica in 2% w/v alginate beads using 2% w/v calcium chloride as crosslinking agent. This formulation resulted in beads with an average size of 3.73 ± 0.04 mm and an encapsulation efficiency of 70%. In vitro, the beads protected the bacteriophages from pH 3 and released them at higher pH. To confirm that this would protect the bacteriophages from gastrointestinal pH changes, we tested the phage infectivity in vivo assay. Using a model chicken (Gallus gallus domesticus) infected with Salmonella Enteritidis, we confirmed that after 3 h of the beads delivery, infective phages were present in the chicken's duodenal and caecal sections. This study demonstrates that our phage formulation is an effective system for release and delivery of bacteriophage S1 against Salmonella Enteritidis with potential use in the poultry sector.

Development of phage delivery by bioencapsulation of artemia nauplii with Edwardsiella tarda phage (ETP-1).

This study proposed that phage-enriched artemia could be a useful tool for transferring phage into the cultured fish (larvae or adult) as a feed, and introduce mode of phage administration and its safety in concern of tissue adaptation for efficient phage therapy in aquatic animals. First, whether Edwardsiella tarda phage (ETP-1) could attach or ingest by the artemia and optimum time period for the ETP-1 enrichment with artemia were investigated. ETP-1 dispersion, abundance and persistency, and zebrafish immune transcriptional responses and histopathology were evaluated after feeding the fish with ETP-1-enriched artemia. Hatched artemia nauplii (36 h) were enriched with 1.90 × 1011 PFUmL-1 of ETP-1, and maintained at 25 °C. The highest enrichment level was obtained after 4 h (3.00 × 109 PFUmL-1), and artemia were alive and active similar to control for 8 h. ETP-1 disseminated dose dependently to all the tissues rapidly (12 h). However, when feeding discontinued, it drastically decreased at day 3 with high abundance and persistency in the spleen (1.02 × 103) followed by the kidney (4.00 × 101) and the gut (1 × 101 PFUmL-1) for highest ETP-1-enriched artemia dose. In contrast, during continuous delivery of ETP-1-enriched artemia, ETP-1 detected in all the tissues (at day 10: gut; 1.90 × 107, kidney; 3.33 × 106, spleen; 5.52 × 105, liver; 6.20 × 104 PFUmL-1mg-1 tissues). Though the phage abundance varied, results indicated that oral fed ETP-1-enriched artemia disperse to the neighboring organs, even the absence of host as phage carrier. Non-significant differences of immune transcriptional and histopathology analysis between ETP-1-enriched artemia fed and controls suggest that no adverse apparent immune stimulation in host occurred, and use of ETP-1 at 1011 PFUmL-1 was safe. With further supportive studies, live artemia-mediated phage delivery method could be used as a promising tool during phage therapy against pathogenic bacteria to control aquatic diseases.

The forgotten tale of Brazilian phage therapy.

The use of bacteriophages to treat bacterial infections (known as phage therapy) is considered a possible solution to the antimicrobial resistance crisis. However, phage therapy is not a new concept. The discovery of phages in the early 20th century was closely tied to clinical practice, and phage therapy quickly spread around the world. The use of phage therapy in South America in the previous century is still shrouded in mystery and has been mentioned only briefly in recent scientific literature. Research on Brazilian reference collections of medical texts showed that Brazil was an important, but so far little-known, player of phage therapy, uncovering interesting priority claims and missing pieces of phage therapy history. Of note, there is the widespread use of phages against bacillary dysentery and staphylococcal infections, with José da Costa Cruz from the Oswaldo Cruz Institute (Rio de Janeiro, Brazil) as Brazil's leading expert and pioneer. This Historical Review about historical phage use in Brazil fills the gaps in our knowledge about the so-called golden years of phage therapy, providing information about successful experiences that can be useful against dangerous pathogens in our time.

Phage Therapy as an Approach to Control Salmonella enterica serotype Enteritidis Infection in Mice.

INTRODUCTION: Salmonella enterica serotype Enteritidis (S. Enteritidis) is a cause of food-borne human illness. Given the prevalence of antibiotic resistance of Salmonella Enteritidis and the lack of antibiotic efficacy in future years, its replacement with other agents is necessary. One of the most useful agents is bacteriophages. METHODS: S. Enteritidis was identified using a multiplex polymerase chain reaction assay. The effective bacteriophages were isolated from hospital wastewater samples. The effects of the bacteriophages were evaluated both in vitro and in vivo. RESULTS: The phage SE20 belonged to the Podoviridae family, and the genome size was 40 kb. The evaluation of phage SE20 at variable pH ranges showed its susceptibility to pH < 3 and pH > 12. The animal model showed that mice infected with S. Enteritidis developed hepatomegaly and splenomegaly, but did not experience gastrointestinal complications after receiving the bacteriophages. CONCLUSIONS: The results of this study suggest that phage SE20 is a promising candidate for controlling salmonellosis caused by Salmonella Enteritidis.

Phage therapy as an approach to control salmonella enterica serotype enteritidis infection in mice

Abstract INTRODUCTION: Salmonella enterica serotype Enteritidis (S. Enteritidis) is a cause of food-borne human illness. Given the prevalence of antibiotic resistance of Salmonella Enteritidis and the lack of antibiotic efficacy in future years, its replacement with other agents is necessary. One of the most useful agents is bacteriophages. METHODS S. Enteritidis was identified using a multiplex polymerase chain reaction assay. The effective bacteriophages were isolated from hospital wastewater samples. The effects of the bacteriophages were evaluated both in vitro and in vivo. RESULTS The phage SE20 belonged to the Podoviridae family, and the genome size was 40 kb. The evaluation of phage SE20 at variable pH ranges showed its susceptibility to pH < 3 and pH > 12. The animal model showed that mice infected with S. Enteritidis developed hepatomegaly and splenomegaly, but did not experience gastrointestinal complications after receiving the bacteriophages. CONCLUSIONS The results of this study suggest that phage SE20 is a promising candidate for controlling salmonellosis caused by Salmonella Enteritidis.

Biotechnological applications of bacteriophages: State of the art.

Bacteriophage particles are the most abundant biological entities on our planet, infecting specific bacterial hosts in every known environment and being major drivers of bacterial adaptive evolution. The study of bacteriophage particles potentially sheds light on the development of new biotechnology products. Bacteriophage therapy, although not new, makes use of strictly lytic phage particles as an alternative in the antimicrobial treatment of resistant bacterial infections and is being rediscovered as a safe method due to the fact that these biological entities devoid of any metabolic machinery do not have affinity to eukaryotic cells. Furthermore, bacteriophage-based vaccination is emerging as one of the most promising preventive strategies. This review paper discusses the biological nature of bacteriophage particles, their mode(s) of action and potential exploitation in modern biotechnology. Topics covered in detail include the potential of bacteriophage particles in human infections (bacteriophage therapy), nanocages for gene delivery, food biopreservation and safety, biocontrol of plant pathogens, phage display, bacterial biosensing devices, vaccines and vaccine carriers, biofilm and bacterial growth control, surface disinfection, corrosion control, together with structural and functional stabilization issues.