Research

30 pages, 6782 KiB

Open AccessEditor’s ChoiceArticle

Characterization of Novel Lytic Myoviridae Phage Infecting Multidrug-Resistant Acinetobacter baumannii and Synergistic Antimicrobial Efficacy between Phage and Sacha Inchi Oil

by Phitchayapak Wintachai and Supayang Piyawan Voravuthikunchai

Pharmaceuticals 2022, 15(3), 291; https://doi.org/10.3390/ph15030291 - 26 Feb 2022

Cited by 10 | Viewed by 3506

Abstract

Multidrug-resistant (MDR) strains of Acinetobacter baumannii have become a major cause of hospital-acquired infections, resulting in an increase in morbidity and mortality worldwide. Many alternative treatments, including phage therapy, are attractive approaches for overcoming problems posed by antibiotic resistance. A newly isolated phage, [...] Read more.

Multidrug-resistant (MDR) strains of Acinetobacter baumannii have become a major cause of hospital-acquired infections, resulting in an increase in morbidity and mortality worldwide. Many alternative treatments, including phage therapy, are attractive approaches for overcoming problems posed by antibiotic resistance. A newly isolated phage, vWUPSU-specific MDR A. baumannii, showed a narrow host range against MDR A. baumannii. This research was conducted to isolate, characterize, and apply the phage with sacha inchi oil as an alternative antimicrobial agent. Genome analysis suggested that phage vWUPSU is a novel phage belonging to the family Myoviridae, order Caudoviridae. This phage prevented biofilm formation and eradicated preformed biofilms in a dose-dependent manner. In addition, a synergistic antimicrobial effect of the interaction between phage vWUPSU and sacha inchi oil on planktonic cells was observed. The combination of phage and sacha inchi oil significantly inhibited and removed biofilms, compared with the effects of either single treatment. The results of this work indicate that phage vWUPSU could potentially be applied to control MDR A. baumannii. The antibacterial and antibiofilm activities of the combination of phage vWUPSU and sacha inchi oil have attracted significant interests in the development of antibacterial phage products as beneficial treatment options. Full article

(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control 2021)

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20 pages, 16596 KiB

Open AccessArticle

Population Dynamics of a Two Phages–One Host Infection System Using Escherichia coli Strain ECOR57 and Phages vB_EcoP_SU10 and vB_EcoD_SU57

by Shazeeda Koonjan, Carlos Cardoso Palacios and Anders S. Nilsson

Pharmaceuticals 2022, 15(3), 268; https://doi.org/10.3390/ph15030268 - 22 Feb 2022

Cited by 1 | Viewed by 2284

Abstract

In this study, we looked at the population dynamics of a two phages-one host system using phages vB_EcoP_SU10 (SU10) and vB_EcoD_SU57 (SU57) and the bacteria Escherichia coli, strain ECOR57. Phage-specific growth curves were observed where infections by SU10 resulted in a moderate [...] Read more.

In this study, we looked at the population dynamics of a two phages-one host system using phages vB_EcoP_SU10 (SU10) and vB_EcoD_SU57 (SU57) and the bacteria Escherichia coli, strain ECOR57. Phage-specific growth curves were observed where infections by SU10 resulted in a moderate production of phages and infections by SU57 resulted in a fast and extensive production of phage progeny. Sequentially adding SU10 followed by SU57 did not produce a significant change in growth rates, whereas adding SU57 followed by SU10 resulted in a decrease in SU10 titer The efficiency of the plating assays showed that ECOR57 exhibited a resistance spectrum after infection by both the single and combined phages. Phage-resistant bacteria exhibited four different morphotypes (i.e., normal, slimy, edgy, and pointy). The normal and edgy morphotypes had a high frequency of developing resistance. Bacterial growth and biofilm assays indicated that the edgy and pointy morphotypes reached a stationary phase faster and produced more biofilm compared to the wild type. These findings suggest that the dynamic structure of phage–bacteria communities dictate resistance evolution and development. Understanding when and how resistances arise and phage(s)–hosts interactions could aid in the design of phage therapy treatments. Full article

(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control 2021)

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19 pages, 2390 KiB

Open AccessArticle

Development of a Phage Cocktail to Target Salmonella Strains Associated with Swine

by Anisha M. Thanki, Viviana Clavijo, Kit Healy, Rachael C. Wilkinson, Thomas Sicheritz-Pontén, Andrew D. Millard and Martha R. J. Clokie

Pharmaceuticals 2022, 15(1), 58; https://doi.org/10.3390/ph15010058 - 02 Jan 2022

Cited by 13 | Viewed by 2499

Abstract

Infections caused by multidrug resistant Salmonella strains are problematic in swine and are entering human food chains. Bacteriophages (phages) could be used to complement or replace antibiotics to reduce infection within swine. Here, we extensively characterised six broad host range lytic Salmonella phages, [...] Read more.

Infections caused by multidrug resistant Salmonella strains are problematic in swine and are entering human food chains. Bacteriophages (phages) could be used to complement or replace antibiotics to reduce infection within swine. Here, we extensively characterised six broad host range lytic Salmonella phages, with the aim of developing a phage cocktail to prevent or treat infection. Intriguingly, the phages tested differed by one to five single nucleotide polymorphisms. However, there were clear phenotypic differences between them, especially in their heat and pH sensitivity. In vitro killing assays were conducted to determine the efficacy of phages alone and when combined, and three cocktails reduced bacterial numbers by ~2 × 10³ CFU/mL within two hours. These cocktails were tested in larvae challenge studies, and prophylactic treatment with phage cocktail SPFM10-SPFM14 was the most efficient. Phage treatment improved larvae survival to 90% after 72 h versus 3% in the infected untreated group. In 65% of the phage-treated larvae, Salmonella counts were below the detection limit, whereas it was isolated from 100% of the infected, untreated larvae group. This study demonstrates that phages effectively reduce Salmonella colonisation in larvae, which supports their ability to similarly protect swine. Full article

(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control 2021)

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14 pages, 1720 KiB

Open AccessFeature PaperArticle

Analysis of Infection Time Courses Shows CII Levels Determine the Frequency of Lysogeny in Phage 186

by Nan Hao, Dylan Agnew, Sandeep Krishna, Ian B. Dodd and Keith E. Shearwin

Pharmaceuticals 2021, 14(10), 998; https://doi.org/10.3390/ph14100998 - 29 Sep 2021

Viewed by 2040

Abstract

Engineered phage with properties optimised for the treatment of bacterial infections hold great promise, but require careful characterisation by a number of approaches. Phage–bacteria infection time courses, where populations of bacteriophage and bacteria are mixed and followed over many infection cycles, can be [...] Read more.

Engineered phage with properties optimised for the treatment of bacterial infections hold great promise, but require careful characterisation by a number of approaches. Phage–bacteria infection time courses, where populations of bacteriophage and bacteria are mixed and followed over many infection cycles, can be used to deduce properties of phage infection at the individual cell level. Here, we apply this approach to analysis of infection of Escherichia coli by the temperate bacteriophage 186 and explore which properties of the infection process can be reliably inferred. By applying established modelling methods to such data, we extract the frequency at which phage 186 chooses the lysogenic pathway after infection, and show that lysogenisation increases in a graded manner with increased expression of the lysogenic establishment factor CII. The data also suggest that, like phage λ, the rate of lysogeny of phage 186 increases with multiple infections. Full article

(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control 2021)

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21 pages, 2788 KiB

Open AccessArticle

Microencapsulation of Bacteriophages Using Membrane Emulsification in Different pH-Triggered Controlled Release Formulations for Oral Administration

by Kerry Richards and Danish J. Malik

Pharmaceuticals 2021, 14(5), 424; https://doi.org/10.3390/ph14050424 - 02 May 2021

Cited by 14 | Viewed by 3063

Abstract

An E.coli-specific phage was encapsulated in three different pH responsive polymer formulations using the process of membrane emulsification. Small 100 µm capsules were fabricated and shown to afford phages suitable acid protection upon exposure to pH 1.5. Selection of polymer formulations allowed [...] Read more.

An E.coli-specific phage was encapsulated in three different pH responsive polymer formulations using the process of membrane emulsification. Small 100 µm capsules were fabricated and shown to afford phages suitable acid protection upon exposure to pH 1.5. Selection of polymer formulations allowed controlled release of phages at pH 5.5, pH 6 and pH 7. Other aspects of phage encapsulation including factors affecting encapsulation yield, release kinetics, acid and storage stability were evaluated. The work presented here would be useful for future evaluation of new therapeutic strategies including microbiome editing approaches allowing pH-triggered release of phages and delivery of encapsulated cargo to different intestinal compartments. The size of the capsules were selected to permit ease of delivery using small bore oral gavage tubes typically used in pre-clinical studies for evaluation of drug substances using small animal vertebrate models such as in mice and rats. Full article

(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control 2021)

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15 pages, 1675 KiB

Open AccessArticle

Synergistic Killing and Re-Sensitization of Pseudomonas aeruginosa to Antibiotics by Phage-Antibiotic Combination Treatment

by Emily Engeman, Helen R. Freyberger, Brendan W. Corey, Amanda M. Ward, Yunxiu He, Mikeljon P. Nikolich, Andrey A. Filippov, Stuart D. Tyner and Anna C. Jacobs

Pharmaceuticals 2021, 14(3), 184; https://doi.org/10.3390/ph14030184 - 25 Feb 2021

Cited by 32 | Viewed by 4320

Abstract

Multidrug-resistant (MDR) Pseudomonas aeruginosa infections pose a serious health threat. Bacteriophage–antibiotic combination therapy is a promising candidate for combating these infections. A 5-phage P. aeruginosa cocktail, PAM2H, was tested in combination with antibiotics (ceftazidime, ciprofloxacin, gentamicin, meropenem) to determine if PAM2H enhances antibiotic [...] Read more.

Multidrug-resistant (MDR) Pseudomonas aeruginosa infections pose a serious health threat. Bacteriophage–antibiotic combination therapy is a promising candidate for combating these infections. A 5-phage P. aeruginosa cocktail, PAM2H, was tested in combination with antibiotics (ceftazidime, ciprofloxacin, gentamicin, meropenem) to determine if PAM2H enhances antibiotic activity. Combination treatment in vitro resulted in a significant increase in susceptibility of MDR strains to antibiotics. Treatment with ceftazidime (CAZ), meropenem, gentamicin, or ciprofloxacin in the presence of the phage increased the number of P. aeruginosa strains susceptible to these antibiotics by 63%, 56%, 31%, and 81%, respectively. Additionally, in a mouse dorsal wound model, seven of eight mice treated with a combination of CAZ and PAM2H for three days had no detectable bacteria remaining in their wounds on day 4, while all mice treated with CAZ or PAM2H alone had ~10⁷ colony forming units (CFU) remaining in their wounds. P. aeruginosa recovered from mouse wounds post-treatment showed decreased virulence in a wax worm model, and DNA sequencing indicated that the combination treatment prevented mutations in genes encoding known phage receptors. Treatment with PAM2H in combination with antibiotics resulted in the re-sensitization of P. aeruginosa to antibiotics in vitro and a synergistic reduction in bacterial burden in vivo. Full article

(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control 2021)

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19 pages, 4607 KiB

Open AccessArticle

A New Phage Lysin Isolated from the Oral Microbiome Targeting Streptococcus pneumoniae

by Imme van der Kamp, Lorraine A. Draper, Muireann K. Smith, Colin Buttimer, R. Paul Ross and Colin Hill

Pharmaceuticals 2020, 13(12), 478; https://doi.org/10.3390/ph13120478 - 19 Dec 2020

Cited by 11 | Viewed by 3832

Abstract

Streptococcus pneumoniae is highly pathogenic and causes several mucosal and invasive infections. Due to the rising number of multidrug-resistant (MDR) strains of S. pneumoniae, new antimicrobials with alternative mechanisms of action are urgently needed. In this study, we identified two new Streptococcal [...] Read more.

Streptococcus pneumoniae is highly pathogenic and causes several mucosal and invasive infections. Due to the rising number of multidrug-resistant (MDR) strains of S. pneumoniae, new antimicrobials with alternative mechanisms of action are urgently needed. In this study, we identified two new Streptococcal phages from the oral microbiome, 23TH and SA01. Their lysins, 23TH_48 and SA01_53, were recombinantly expressed, characterized and tested for their lethality. SA01_53 was found to only lyse its host strain of S. anginosus, while 23TH_48 was found to possess a broader lytic activity beyond its host strain of S. infantis, with several S. pneumoniae isolates sensitive to its lytic activity. 23TH_48 at a concentration of five activity units per mL (U/mL) was found to reduce cell counts of S. pneumoniae DSM 24048 by 4 log₁₀ colony forming units per mL (CFU/mL) within 1 h and effectively prevented and destroyed biofilms of S. pneumoniae R6 at concentrations of 228.8 ng/µL and 14.3 ng/µL, respectively. Given its high lytic activity, 23TH_48 could prove to be a promising candidate to help combat pneumococcal infections. Full article

(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control 2021)

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Review

Jump to: Research, Other

36 pages, 1229 KiB

Open AccessReview

The Age of Phage: Friend or Foe in the New Dawn of Therapeutic and Biocontrol Applications?

by Ahmad Y. Hassan, Janet T. Lin, Nicole Ricker and Hany Anany

Pharmaceuticals 2021, 14(3), 199; https://doi.org/10.3390/ph14030199 - 28 Feb 2021

Cited by 36 | Viewed by 13914

Abstract

Extended overuse and misuse of antibiotics and other antibacterial agents has resulted in an antimicrobial resistance crisis. Bacteriophages, viruses that infect bacteria, have emerged as a legitimate alternative antibacterial agent with a wide scope of applications which continue to be discovered and refined. [...] Read more.

Extended overuse and misuse of antibiotics and other antibacterial agents has resulted in an antimicrobial resistance crisis. Bacteriophages, viruses that infect bacteria, have emerged as a legitimate alternative antibacterial agent with a wide scope of applications which continue to be discovered and refined. However, the potential of some bacteriophages to aid in the acquisition, maintenance, and dissemination of negatively associated bacterial genes, including resistance and virulence genes, through transduction is of concern and requires deeper understanding in order to be properly addressed. In particular, their ability to interact with mobile genetic elements such as plasmids, genomic islands, and integrative conjugative elements (ICEs) enables bacteriophages to contribute greatly to bacterial evolution. Nonetheless, bacteriophages have the potential to be used as therapeutic and biocontrol agents within medical, agricultural, and food processing settings, against bacteria in both planktonic and biofilm environments. Additionally, bacteriophages have been deployed in developing rapid, sensitive, and specific biosensors for various bacterial targets. Intriguingly, their bioengineering capabilities show great promise in improving their adaptability and effectiveness as biocontrol and detection tools. This review aims to provide a balanced perspective on bacteriophages by outlining advantages, challenges, and future steps needed in order to boost their therapeutic and biocontrol potential, while also providing insight on their potential role in contributing to bacterial evolution and survival. Full article

(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control 2021)

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Other

Jump to: Research, Review

7 pages, 10024 KiB

Open AccessCase Report

Successful Use of Salvage Bacteriophage Therapy for a Recalcitrant MRSA Knee and Hip Prosthetic Joint Infection

by Jonathan Schoeffel, Elizabeth Wenqian Wang, Dustin Gill, Joseph Frackler, Bri’Anna Horne, Theodore Manson and James B. Doub

Pharmaceuticals 2022, 15(2), 177; https://doi.org/10.3390/ph15020177 - 31 Jan 2022

Cited by 11 | Viewed by 2870

Abstract

Prosthetic joint infections are a serious complication of joint replacement surgery due to the significant morbidity and financial burden that is associated with conventional treatments. When patients fail the gold standard two-stage revision surgery, very limited, well-defined standardized approaches are available. Herein, we [...] Read more.

Prosthetic joint infections are a serious complication of joint replacement surgery due to the significant morbidity and financial burden that is associated with conventional treatments. When patients fail the gold standard two-stage revision surgery, very limited, well-defined standardized approaches are available. Herein, we discuss the case of a sixty-four-year-old woman who had a recalcitrant MRSA prosthetic joint infection of her knee and hip that failed repeated conventional surgical and medical treatments. Only after receiving intraoperative and intravenous bacteriophage therapy was the patient able to achieve cure of her prosthetic joint infections, as demonstrated by the lack of clinical recurrence and sterility of intraoperative cultures while off antibiotics. This case reinforces that bacteriophage therapy holds promise in the treatment of prosthetic joint infections and more specifically in complicated cases who have failed conventional surgical and medical interventions. Full article

(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control 2021)

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25 pages, 434 KiB

Open AccessFeature PaperOpinion

Phage Therapy in the 21st Century: Is There Modern, Clinical Evidence of Phage-Mediated Efficacy?

by Stephen T. Abedon, Katarzyna M. Danis-Wlodarczyk and Diana R. Alves

Pharmaceuticals 2021, 14(11), 1157; https://doi.org/10.3390/ph14111157 - 13 Nov 2021

Cited by 29 | Viewed by 4375

Abstract

Many bacteriophages are obligate killers of bacteria. That this property could be medically useful was first recognized over one hundred years ago, with 2021 being the 100-year anniversary of the first clinical phage therapy publication. Here we consider modern use of phages in [...] Read more.

Many bacteriophages are obligate killers of bacteria. That this property could be medically useful was first recognized over one hundred years ago, with 2021 being the 100-year anniversary of the first clinical phage therapy publication. Here we consider modern use of phages in clinical settings. Our aim is to answer one question: do phages serve as effective anti-bacterial infection agents when used clinically? An important emphasis of our analyses is on whether phage therapy-associated anti-bacterial infection efficacy can be reasonably distinguished from that associated with often coadministered antibiotics. We find that about half of 70 human phage treatment reports—published in English thus far in the 2000s—are suggestive of phage-mediated anti-bacterial infection efficacy. Two of these are randomized, double-blinded, infection-treatment studies while 14 of those studies, in our opinion, provide superior evidence of a phage role in observed treatment successes. Roughly three-quarters of these potentially phage-mediated outcomes are based on microbiological as well as clinical results, with the rest based on clinical success. Since many of these phage treatments are of infections for which antibiotic therapy had not been successful, their collective effectiveness is suggestive of a valid utility in employing phages to treat otherwise difficult-to-cure bacterial infections. Full article

(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control 2021)

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25 pages, 3870 KiB

Open AccessEditor’s ChoiceOpinion

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

by Stephen T. Abedon, Katarzyna M. Danis-Wlodarczyk and Daniel J. Wozniak

Pharmaceuticals 2021, 14(10), 1019; https://doi.org/10.3390/ph14101019 - 03 Oct 2021

Cited by 66 | Viewed by 7203

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control 2021)

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10 pages, 1158 KiB

Open AccessCase Report

Successful Treatment of a Recalcitrant Staphylococcus epidermidis Prosthetic Knee Infection with Intraoperative Bacteriophage Therapy

by James B. Doub, Vincent Y. Ng, Eleanor Wilson, Lorenzo Corsini and Benjamin K. Chan

Pharmaceuticals 2021, 14(3), 231; https://doi.org/10.3390/ph14030231 - 08 Mar 2021

Cited by 24 | Viewed by 5667

Abstract

Here, we present a case of a 79-year-old female with a recalcitrant Staphylococcal epidermidis prosthetic knee infection that was successfully treated with a single dose of adjuvant intra-articular bacteriophage therapy after debridement and implant retention surgery. The bacteriophage used in this case, PM448, [...] Read more.

Here, we present a case of a 79-year-old female with a recalcitrant Staphylococcal epidermidis prosthetic knee infection that was successfully treated with a single dose of adjuvant intra-articular bacteriophage therapy after debridement and implant retention surgery. The bacteriophage used in this case, PM448, is the first ɛ² bacteriophage to be used in vivo. Currently the patient is without evidence of clinical recurrence and, interestingly, the patient had also suffered from debilitating aplastic anemia for over 2 years, which is recovering since receiving adjuvant bacteriophage therapy. Full article

(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control 2021)

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