Bacteriophage and Endolysin Encapsulation Systems: A Promising Strategy to Improve Therapeutic Outcomes

Gondil, Vijay Singh; Chhibber, Sanjay

doi:10.3389/fphar.2021.675440

Cited by 30 publications

(24 citation statements)

References 34 publications

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“…Endolysins, being proteins and showing labile enzymatic activity suffer for similar or even more additional barriers than parent phages which include issue of stability, retention of their lytic spectrum at the infection site , in-vivo half-life etc. ( Gondil and Chhibber, 2021 ). However, unlike phage encapsulation, endolysin delivery systems based research especially involving use of nanotechnology is still in the early stages.…”

Section: Nanotechnology To the Rescuementioning

confidence: 99%

Nanotechnology Based Approaches in Phage Therapy: Overcoming the Pharmacological Barriers

Kaur¹,

Kumari²,

Negi

et al. 2021

Front. Pharmacol.

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With the emergence and spread of global antibiotic resistance and the need for searching safer alternatives, there has been resurgence in exploring the use of bacteriophages in the treatment of bacterial infections referred as phage therapy. Although modern phage therapy has come a long way as demonstrated by numerous efficacy studies but the fact remains that till date, phage therapy has not received regulatory approval for human use (except for compassionate use).Thus, to hit the clinical market, the roadblocks need to be seriously addressed and gaps mended with modern solution based technologies. Nanotechnology represents one such ideal and powerful tool for overcoming the pharmacological barriers (low stability, poor in-vivo retention, targeted delivery, neutralisation by immune system etc.) of administered phage preparations.In literature, there are many review articles on nanotechnology and bacteriophages but these are primarily focussed on highlighting the use of lytic and temperate phages in different fields of nano-medicine such as nanoprobes, nanosensors, cancer diagnostics, cancer cell targeting, drug delivery through phage receptors, phage display etc. Reviews specifically focused on the use of nanotechnology driven techniques strictly to improve phage therapy are however limited. Moreover, these review if present have primarily focussed on discussing encapsulation as a primary method for improving the stability and retention of phage(s) in the body.With new advances made in the field of nanotechnology, approaches extend from mere encapsulation to recently adopted newer strategies. The present review gives a detailed insight into the more recent strategies which include 1) use of lipid based nano-carriers (liposomes, transfersomes etc.) 2) adopting microfluidic based approach, surface modification methods to further enhance the efficiency and stability of phage loaded liposomes 3) Nano- emulsification approach with integration of microfluidics for producing multiple emulsions (suitable for phage cocktails) with unique control over size, shape and drop morphology 4) Phage loaded nanofibers produced by electro-spinning and advanced core shell nanofibers for immediate, biphasic and delayed release systems and 5) Smart release drug delivery platforms that allow superior control over dosing and phage release as and when required. All these new advances are aimed at creating a suitable housing system for therapeutic bacteriophage preparations while targeting the multiple issues of phage therapy i.e., improving phage stability and titers, improving in-vivo retention times, acting as suitable delivery systems for sustained release at target site of infection, improved penetration into biofilms and protection from immune cell attack. The present review thus aims at giving a complete insight into the recent advances (2010 onwards) related to various nanotechnology based approaches to address the issues pertaining to phage therapy. This is essential for improving the overall therapeutic index and success of phage therapy for future clinical approval.

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Section: Nanotechnology To the Rescuementioning

confidence: 99%

Nanotechnology Based Approaches in Phage Therapy: Overcoming the Pharmacological Barriers

Kaur¹,

Kumari²,

Negi

et al. 2021

Front. Pharmacol.

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show abstract

“…These characteristics were explored in Section 4. Multimodular proteins, proteins with different catalytic and cell-binding domains, lead to considerable variations in antimicrobial activity and will probably affect formulation design and pharmacokinetics [86]. These characteristics point to the idea that endolysin systems need to be carefully designed for each endolysin.…”

Section: Limitations Of Endolysin Therapymentioning

confidence: 99%

“…Considering these four limitations, especially the individuality of endolysin treatments and scale-up efforts, the cost of the development of endolysin-based drugs is currently higher than that of conventional antibiotics [86]. Despite these limitations, endolysinsbased treatments are expected to enter clinical trials in a near future.…”

Section: Limitations Of Endolysin Therapymentioning

confidence: 99%

Current Status of Endolysin-Based Treatments against Gram-Negative Bacteria

2021

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The prevalence of multidrug-resistant Gram-negative bacteria is a public health concern. Bacteriophages and bacteriophage-derived lytic enzymes have been studied in response to the emergence of multidrug-resistant bacteria. The availability of tRNAs and endolysin toxicity during recombinant protein expression is circumvented by codon optimization and lower expression levels using inducible pET-type plasmids and controlled cultivation conditions, respectively. The use of polyhistidine tags facilitates endolysin purification and alters antimicrobial activity. Outer membrane permeabilizers, such as organic acids, act synergistically with endolysins, but some endolysins permeate the outer membrane of Gram-negative bacteria per se. However, the outer membrane permeation mechanisms of endolysins remain unclear. Other strategies, such as the co-administration of endolysins with polymyxins, silver nanoparticles, and liposomes confer additional outer membrane permeation. Engineered endolysins comprising domains for outer membrane permeation is also a strategy used to overcome the current challenges on the control of multidrug-resistant Gram-negative bacteria. Metagenomics is a new strategy for screening endolysins with interesting antimicrobial properties from uncultured phage genomes. Here, we review the current state of the art on the heterologous expression of endolysin, showing the potential of bacteriophage endolysins in controlling bacterial infections.

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“…In particular, the development of resistance appears to be happening at a significantly decreased rate when phage-derived enzymes are used instead of bacteriophages [ 10 ]. The most well studied of such enzymes are endolysins that degrade the peptidoglycan of the bacterial host’s cell wall; these enzymes have previously proven effective in controlling bacterial infections and a number are used commercially, e.g., phage enzyme preparations produced by Armata, Micreos, and Intralytix [ 11 , 12 ]. Another group of phage proteins with a significant therapeutic potential are polysaccharide depolymerases [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Novel Phage-Derived Depolymerase with Activity against Proteus mirabilis Biofilms

et al. 2021

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The adherence of Proteus mirabilis to the surface of urinary catheters leads to colonization and eventual blockage of the catheter lumen by unique crystalline biofilms produced by these opportunistic pathogens, making P. mirabilis one of the leading causes of catheter-associated urinary tract infections. The Proteus biofilms reduce efficiency of antibiotic-based treatment, which in turn increases the risk of antibiotic resistance development. Bacteriophages and their enzymes have recently become investigated as alternative treatment options. In this study, a novel Proteus bacteriophage (vB_PmiS_PM-CJR) was isolated from an environmental sample and fully characterized. The phage displayed depolymerase activity and the subsequent genome analysis revealed the presence of a pectate lyase domain in its tail spike protein. The protein was heterologously expressed and purified; the ability of the purified tail spike to degrade Proteus biofilms was tested. We showed that the application of the tail spike protein was able to reduce the adherence of bacterial biofilm to plastic pegs in a MBEC (minimum biofilm eradication concentration) assay and improve the survival of Galleria mellonella larvae infected with Proteus mirabilis. Our study is the first to successfully isolate and characterize a biofilm depolymerase from a Proteus phage, demonstrating the potential of this group of enzymes in treatment of Proteus infections.

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Bacteriophage and Endolysin Encapsulation Systems: A Promising Strategy to Improve Therapeutic Outcomes

Cited by 30 publications

References 34 publications

Nanotechnology Based Approaches in Phage Therapy: Overcoming the Pharmacological Barriers

Nanotechnology Based Approaches in Phage Therapy: Overcoming the Pharmacological Barriers

Current Status of Endolysin-Based Treatments against Gram-Negative Bacteria

Novel Phage-Derived Depolymerase with Activity against Proteus mirabilis Biofilms

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