A review on re-emerging bacteriophage therapy in the era of XDR

In the present medicine world antibiotic resistance is one of the key threats to universal health coverage.Researchers continue to work hard to combat this global health concern.Phage therapy,an age-old practice during the early twentieth century,was outshined by the discovery of antibiotics.With the advent of widespread antibiotic resistance,phage therapy has again redeemed itself as a potential alternative owing to its adeptness to target bacteria precisely.Limited side effects,the ability to migrate to different body organs,a distinct mode of action,and proliferation at the infection site,make phages a profitable candidate to replace conventional antibiotics.The progressive outcome of numerous in vitro studies and case reports has validated the clinical efficacy of phage therapy.The bright perspective of using phages to treat bacterial infections has fueled enormous medical research to exploit their potential as therapeutics.The gaps in the information about phages and the lack of consent for clinical trials is major hurdle for consideration of phage therapy.Crafting phage therapy as a reality in medicine requires a coordinated effort from different fraternities.With this review,we aim to emphasize the importance of phage therapy in modern medicine.This review explains their historical journey,basic phage biology,cross-talk with the host immunity,obstacles with phage therapy,and their possible remedies.Comprehensive data on the various significant clinical trials of phage therapy has been presented.We evaluated the efficacy of antibiotics and phage therapy in part and in combination,along with recent progress and future perspectives of phage therapy.

Pharmacological and Immunological Aspects of Phage Therapy

Bacteriophages,or viruses of microbes,when used as a medical strategy,might be able to solve the current crisis mankind faces with the increasing number of pathogens being antibiotic-resistant,where chemical drugs seized to show any therapeutic effect.The socalled phage therapy may be one of the most promising alternatives to treat infections caused by antibiotic-resistant bacteria,which are killed after infection by a phage.While phages that destroy the host by lysis are chosen for therapy,many pharmacological and immunological aspects of phages as medicines have not been established so far.The immune system plays an important role in a process called phage acceptance where both,innate and adaptive immune responses of the host are involved.However,not only medical aspects but also social ones such as lacking public awareness or acceptance,and lack of structured regulatory guidelines are challenges that have to be addressed in the near future to establish phage therapy as a reliable and safe alternative for the treatment of infections.This review focuses on the unique pharmacological and immunological aspects of phages used in therapy.

Bacteriophages as antimicrobial agents against major pathogens in swine： a review

In recent years, the development of antibiotic resistant bacteria has become a global concern which has prompted research into the development of alternative disease control strategies for the swine industry. Bacteriophages （viruses that infect bacteria） offer the prospect of a sustainable alternative approach against bacterial pathogens with the flexibility of being applied therapeutically or for biological control purposes. This paper reviews the use of phages as an antimicrobial strategy for controlling critical pathogens including Salmonella and Eschefich[a coli with an emphasis on the application of phages for improving performance and nutrient digestibility in swine operations as well as in controlling zoonotic human diseases by reducing the bacterial load spread from pork products to humans through the meat,

Defense and anti-defense mechanisms of bacteria and bacteriophages

In the post-antibiotic era,the overuse of antimicrobials has led to a massive increase in antimicrobial resistance,leaving medical doctors few or no treatment options to fight infections caused by superbugs.The use of bacteriophages is a promising alternative to treat infections,supplementing or possibly even replacing antibiotics.Using phages for therapy is possible,since these bacterial viruses can kill bacteria specifically,causing no harm to the normal flora.However,bacteria have developed a multitude of sophisticated and complex ways to resist infection by phages,including abortive infection and the clustered regularly interspersed short palindromic repeats(CRISPR)/CRISPR-associated(Cas)system.Phages also can evolve and acquire new anti-defense strategies to continue predation.An in-depth exploration of both defense and anti-defense mechanisms would contribute to optimizing phage therapy,while we would also gain novel insights into the microbial world.In this paper,we summarize recent research on bacterial phage resistance and phage anti-defense mechanisms,as well as collaborative win-win systems involving both virus and host.

Characterization of bacteriophage BUCT631 lytic for K1 Klebsiella pneumoniae and its therapeutic efficacy in Galleria mellonella larvae

Severe infections caused by multidrug-resistant Klebsiella pneumoniae(K.pneumoniae)highlight the need for new therapeutics with activity against this pathogen.Phage therapy is an alternative treatment approach for multidrug-resistant K.pneumoniae infections.Here,we report a novel bacteriophage(phage)BUCT631 that can specifically lyse capsule-type K1 K.pneumoniae.Physiological characterization revealed that phage BUCT631 could rapidly adsorb to the surface of K.pneumoniae and form an obvious halo ring,and it had relatively favorable thermal stability(4–50C)and pH tolerance(pH?4–12).In addition,the optimal multiplicity of infection(MOI)of phage BUCT631 was 0.01,and the burst size was approximately 303 PFU/cell.Genomic analysis showed that phage BUCT631 has double-stranded DNA(total length of 44,812 bp)with a G t C content of 54.1%,and the genome contains 57 open reading frames(ORFs)and no virulence or antibiotic resistance related genes.Based on phylogenetic analysis,phage BUCT631 could be assigned to a new species in the genus Drulisvirus of the subfamily Slopekvirinae.In addition,phage BUCT631 could quickly inhibit the growth of K.pneumoniae within 2 h in vitro and significantly elevated the survival rate of K.pneumoniae infected Galleria mellonella larvae from 10%to 90%in vivo.These studies suggest that phage BUCT631 has promising potential for development as a safe alternative for control and treatment of multidrug-resistant K.pneumoniae infection.

Phage engineering： how advances in molecular biology and synthetic biology are being utilized to enhance the therapeutic potential of bacteriophages

Background： The therapeutic potential of bacteriophages has been debated since their first isolation and characterisation in the early 20th century. However, a lack of consistency in application and observed efficacy during their early use meant that upon the discovery of antibiotic compounds research in the field of phage therapy quickly slowed. The rise of antibiotic resistance in bacteria and improvements in our abilities to modify and manipulate DNA, especially in the context of small viral genomes, has led to a recent resurgence of interest in utilising phage as antimicrobial therapeutics. Results： In this article a number of results from the literature that have aimed to address key issues regarding the utility and efficacy of phage as antimicrobial therapeutics utilising molecular biology and synthetic biology approaches will be introduced and discussed, giving a general view of the recent progress in the field. Conclusions： Advances in molecular biology and synthetic biology have enabled rapid progress in the field of phage engineering, with this article highlighting a number of promising strategies developed to optimise phages for the treatment of bacterial disease. Whilst many of the same issues that have historically limited the use of phages as therapeutics still exist, these modifications, or combinations thereof, may form a basis upon which future advances can be built. A focus on rigorous in vivo testing and investment in clinical trials for promising candidate phages may be required for the field to truly mature, but there is renewed hope that the potential benefits of phage therapy may finally be realised.