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A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Bacteriophages".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 46795

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Dr. Carla Pereira

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Department of Biology and CESAM, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal
Interests: bacteriophages; phage therapy; pathogenic bacteria; multidrug resistance bacteria; alternative approaches to antibiotics
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Special Issue Information

Dear Colleagues,

Bacteriophages were discovered in the early 1920s; however, poor understanding of the mechanisms underlying bacterial pathogenesis and the nature of bacteriophage-host interactions, led to a succession of badly designed and executed experiments. This method of antimicrobial treatment was used to treat and prevent bacterial infection diseases both in the former Soviet Union and Eastern Europe, but it was abandoned by the West in the 1940s with the advent of chemical antibiotics. The emergence of pathogenic bacteria resistant to antibiotics, has motivated the scientific community to re-evaluate bacteriophage therapy as a valid option for the treatment of bacterial infections. In recent years, several reports have been published about the successful use of bacteriophages in different fields such as veterinary, agriculture, food safety, aquaculture, and human health. However, this technology is still in development and there are challenges to overcome before bacteriophages can be widely used to control pathogenic bacteria.

This Special Issue of "Phage Therapy to Control Pathogenic Bacteria " will publish the most recent advances in bacteriophage research for bacterial disease control in different areas (veterinary medicine, food industry, agriculture, aquaculture, and human medicine).

Dr. Carla Pereira
Guest Editor

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Keywords

bacteriophages
bacteriophage therapy
human infections
animal infections
plant infections
phage pharmacokinetics
combination therapies
biofilm control
phage resistance

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Published Papers (10 papers)

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Research

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16 pages, 2415 KiB

Open AccessArticle

Phage Targeting Streptococcus mutans In Vitro and In Vivo as a Caries-Preventive Modality

by Amit Wolfoviz-Zilberman, Reut Kraitman, Ronen Hazan, Michael Friedman, Yael Houri-Haddad and Nurit Beyth

Antibiotics 2021, 10(8), 1015; https://doi.org/10.3390/antibiotics10081015 - 21 Aug 2021

Cited by 13 | Viewed by 3904

Abstract

Dental caries is a common infectious disease worldwide. Current conventional therapies lack specific antimicrobial effects against Streptococcus mutans, a key bacterium that induces caries. A promising alternative approach is bacteriophage (phage) therapy. Recently, SMHBZ8 phage targeting S. mutans was isolated and characterized. The aim of this study was to evaluate the caries-prevention efficacy of SMHBZ8 using in vitro and in vivo caries models. Hemi-mandibles dissected from euthanized healthy mice were subjected to caries-promoting conditions in vitro. Jaws treated with phage therapy in suspension and in formulation with a sustained-release delivery system showed no carious lesions, similar to control and chlorhexidine-treated jaws. Subsequently, SMHBZ8 phage suspension also prevented carious lesion development in a murine caries model in vivo. In both models, caries lesions were analyzed clinically and radiographically by µCT scans. This study shows how SMHBZ8 phage therapy targeting S. mutans can serve as an efficient caries-prevention modality, in suspension or with a sustained-release delivery system, by in vitro and in vivo mouse models. Full article

(This article belongs to the Special Issue Phage Therapy to Control Pathogenic Bacteria)

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16 pages, 2358 KiB

Open AccessArticle

Application of the Resazurin Cell Viability Assay to Monitor Escherichia coli and Salmonella Typhimurium Inactivation Mediated by Phages

by Pedro Costa, Ana T. P. C. Gomes, Márcia Braz, Carla Pereira and Adelaide Almeida

Antibiotics 2021, 10(8), 974; https://doi.org/10.3390/antibiotics10080974 - 12 Aug 2021

Cited by 25 | Viewed by 6994

Abstract

Bacterial inactivation using bacteriophages (or phages) has emerged as an effective solution for bacterial infections, but the screening methods used to evaluate the effectiveness of the phages to inactivate bacteria are not fast, reliable or precise enough. The efficiency of bacterial inactivation by phages has been evaluated by monitoring bacterial concentration either by counting colony-forming units (CFU), a laborious and time-consuming method, or by monitoring the optical density (OD), a less sensitive method. In this study, the resazurin cell viability assay was used to monitor the viability of bacteria from different genera during the inactivation by different phages, and the results were compared with the standard methods used to assess bacterial inactivation. The results showed that the resazurin colorimetric cell viability assay produces similar results to the standard method of colony-counting and giving, and also more sensitive results than the OD method. The resazurin assay can be used to quickly obtain the results of the cell viability effect profile using two different bacterial strains and several different phages at the same time, which is extremely valuable in screening studies. Moreover, this methodology is established as an effective, accurate and rapid method when compared to the ones widely used to monitor bacterial inactivation mediated by phages. Full article

(This article belongs to the Special Issue Phage Therapy to Control Pathogenic Bacteria)

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16 pages, 2153 KiB

Open AccessArticle

Successful Intratracheal Treatment of Phage and Antibiotic Combination Therapy of a Multi-Drug Resistant Pseudomonas aeruginosa Murine Model

by Christopher Duplessis, Jonathan M. Warawa, Matthew B. Lawrenz, Matthew Henry and Biswajit Biswas

Antibiotics 2021, 10(8), 946; https://doi.org/10.3390/antibiotics10080946 - 5 Aug 2021

Cited by 14 | Viewed by 3766

Abstract

Background: Pseudomonas aeruginosa (PsA) is a common etiology of bacteria-mediated lower respiratory tract infections, including pneumonia, hospital acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP). Given the paucity of novel antibiotics in our foreseeable pipeline, developing novel non-antibiotic antimicrobial therapies saliently targeting drug resistant PsA isolates remains a priority. Lytic bacteriophages (or phages) have come under scrutiny as a potential antimicrobial for refractory bacterial infections. We evaluated intratracheally and intraperitoneally (IP) administered phage therapy (with/without meropenem) in an acute immunocompromised mouse model of multi-drug resistant (MDR) PsA pulmonary infection. The MDR P. aeruginosa respiratory disease model used in these studies was developed to investigate novel therapies that might have efficacy as either monotherapies or as combination therapy with meropenem. Methods: We utilized eight-week-old, 18 g BALB/cJ female mice and an MDR strain of PsA (UNC-D). Mice were immunosuppressed with cyclophosphamide. We employed a three-phage cocktail targeting PsA (PaAH2ΦP (103), PaBAP5Φ2 (130), and PaΦ (134)), confirmed to exhibit in vitro suppression of the infecting isolate out to 45 h. Suppression was confirmed with phages acting in isolation and in combination with meropenem. Results: IP administration of phage did not protect mice from death. A one-time delivery of phage directly to the lungs via a single intubation-mediated, intratracheal (IMIT) instillation protected mice from lethal infection. Protection was observed despite delaying therapy out to 6 h. Finally, we observed that, by slowing the progression of infection by treatment with a sub-efficacious dose of meropenem, we could protect the mice from lethal infection via IP phage administration coupled to meropenem, observing partial additive effects of phage–antibiotic combination therapy. Conclusions: A personalized phage cocktail administered via IMIT exhibits high therapeutic efficacy, despite delayed treatment of 6 h in a lethal MDR PsA pneumonia model. IP phage alone did not forestall mortality, but exhibited efficacy when combined with meropenem and IMIT-administered phage. These additive effects of combined IP phage and meropenem confirm that phage may indeed reach the lung bed via the systemic circulation and protect mice if the infection is not too acute. Therefore, adjunctive phage therapy with concerted attention to identifying optimal phage targeting of the infecting isolate in vitro may exhibit transformative potential for combating the specter of MDR bacterial infections. Phage should serve as an integral component of a four-pronged approach coupled with antibiotics, source control, and immune optimization. Full article

(This article belongs to the Special Issue Phage Therapy to Control Pathogenic Bacteria)

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16 pages, 11140 KiB

Open AccessArticle

Pseudomonas aeruginosa PAO 1 In Vitro Time–Kill Kinetics Using Single Phages and Phage Formulations—Modulating Death, Adaptation, and Resistance

by Ana Mafalda Pinto, Alberta Faustino, Lorenzo M. Pastrana, Manuel Bañobre-López and Sanna Sillankorva

Antibiotics 2021, 10(7), 877; https://doi.org/10.3390/antibiotics10070877 - 19 Jul 2021

Cited by 9 | Viewed by 4008

Abstract

Pseudomonas aeruginosa is responsible for nosocomial and chronic infections in healthcare settings. The major challenge in treating P. aeruginosa-related diseases is its remarkable capacity for antibiotic resistance development. Bacteriophage (phage) therapy is regarded as a possible alternative that has, for years, attracted attention for fighting multidrug-resistant infections. In this work, we characterized five phages showing different lytic spectrums towards clinical isolates. Two of these phages were isolated from the Russian Microgen Sextaphage formulation and belong to the Phikmvviruses, while three Pbunaviruses were isolated from sewage. Different phage formulations for the treatment of P. aeruginosa PAO1 resulted in diversified time–kill outcomes. The best result was obtained with a formulation with all phages, prompting a lower frequency of resistant variants and considerable alterations in cell motility, resulting in a loss of 73.7% in swimming motility and a 79% change in swarming motility. These alterations diminished the virulence of the phage-resisting phenotypes but promoted their growth since most became insensitive to a single or even all phages. However, not all combinations drove to enhanced cell killings due to the competition and loss of receptors. This study highlights that more caution is needed when developing cocktail formulations to maximize phage therapy efficacy. Selecting phages for formulations should consider the emergence of phage-resistant bacteria and whether the formulations are intended for short-term or extended antibacterial application. Full article

(This article belongs to the Special Issue Phage Therapy to Control Pathogenic Bacteria)

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20 pages, 2480 KiB

Open AccessArticle

Bacteriophages with Potential to Inactivate Aeromonas hydrophila in Cockles: In Vitro and In Vivo Preliminary Studies

by João Duarte, Carla Pereira, Pedro Costa and Adelaide Almeida

Antibiotics 2021, 10(6), 710; https://doi.org/10.3390/antibiotics10060710 - 12 Jun 2021

Cited by 17 | Viewed by 3510

Abstract

The recurrent emergence of infection outbreaks associated with shellfish consumption is of extreme importance for public health. The present study investigated the potential application of phages AH-1, AH-4, and AH-5 to inactivate Aeromonas hydrophila, a causative agent of infections in humans associated with bivalve shellfish consumption. The inactivation of A. hydrophila was assessed in vitro, using a liquid culture medium, and in vivo, using artificially contaminated cockles with A. hydrophila ATCC 7966. In the in vitro experiments, all phages were effective against A. hydrophila, but phage AH-1 (with a maximum reduction of 7.7 log colonies forming units CFU/mL) was more effective than phages AH-4 and AH-5 (with reductions of 4.9 and 4.5 log CFU/mL, respectively). The cocktails AH-1/AH-4, AH-1/AH-5, AH-4/AH-5, and AH-1/AH-4/AH-5 were slightly more effective than the single phage suspensions. The phages presented a low emergence rate of phage-resistant mutants. When artificially contaminated cockles were treated in static seawater with phage AH-1, around 44% of the added A. hydrophila (1.0 log CFU/g) was inactivated. The results of this study suggest that phage therapy can be an effective alternative to control human pathogenic bacteria during depuration. Full article

(This article belongs to the Special Issue Phage Therapy to Control Pathogenic Bacteria)

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9 pages, 226 KiB

Open AccessCommunication

Low Immunogenicity of Intravesical Phage Therapy for Urogenitary Tract Infections

by Sławomir Letkiewicz, Marzanna Łusiak-Szelachowska, Ryszard Międzybrodzki, Maciej Żaczek, Beata Weber-Dąbrowska and Andrzej Górski

Antibiotics 2021, 10(6), 627; https://doi.org/10.3390/antibiotics10060627 - 25 May 2021

Cited by 8 | Viewed by 2961

Abstract

Patients with chronic urinary and urogenital multidrug resistant bacterial infections received phage therapy (PT) using intravesical or intravesical and intravaginal phage administration. A single course of PT did not induce significant serum antibody responses against administered phage. Whilst the second cycle of PT caused a significant increase in antibody levels, they nevertheless remained quite low. These data combined with good therapy results achieved in some patients suggest that this mode of PT may be an efficient means of therapy for urogenital infections and a reliable model for a clinical trial of PT. Full article

(This article belongs to the Special Issue Phage Therapy to Control Pathogenic Bacteria)

13 pages, 3549 KiB

Open AccessArticle

Phage PPPL-1, A New Biological Agent to Control Bacterial Canker Caused by Pseudomonas syringae pv. actinidiae in Kiwifruit

by Yu-Rim Song, Nguyen Trung Vu, Jungkum Park, In Sun Hwang, Hyeon-Ju Jeong, Youn-Sup Cho and Chang-Sik Oh

Antibiotics 2021, 10(5), 554; https://doi.org/10.3390/antibiotics10050554 - 10 May 2021

Cited by 16 | Viewed by 5235

Abstract

Pseudomonas syringae pv. actinidiae (Psa) is a Gram-negative bacterium that causes bacterial canker disease in kiwifruit. Copper or antibiotics have been used in orchards to control this disease, but the recent emergence of antibiotic-resistant Psa has called for the development of a new control agent. We previously reported that the bacteriophage (or phage) PPPL-1 showed antibacterial activity for both biovar 2 and 3 of Psa. To investigate the possibility of PPPL-1 to control bacterial canker in kiwifruit, we further tested the efficacy of PPPL-1 and its phage cocktail with two other phages on suppressing disease development under greenhouse conditions using 6 weeks old kiwifruit plants. Our results showed that the disease control efficacy of PPPL-1 treatment was statistically similar to those of phage cocktail treatment or Agrimycin^TM, which contains streptomycin and oxytetracycline antibiotics as active ingredients. Moreover, PPPL-1 could successfully kill streptomycin-resistant Psa isolates, of which the treatment of Buramycin^TM carrying only streptomycin as an active ingredient had no effect in vitro. The phage PPPL-1 was further characterized, and stability assays showed that the phage was stable in the field soil and at low temperature of 0 ± 2 °C. In addition, the phage could be scaled up quickly up to 10¹⁰ pfu/mL at 12 h later from initial multiplicity of infection of 0.000005. Our results indicate that PPPL-1 phage is a useful candidate as a biocontrol agent and could be a tool to control the bacterial canker in kiwifruit by Psa infection in the field conditions. Full article

(This article belongs to the Special Issue Phage Therapy to Control Pathogenic Bacteria)

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10 pages, 587 KiB

Open AccessArticle

An Assessment of the Viability of Lytic Phages and Their Potency against Multidrug Resistant Escherichia coli O177 Strains under Simulated Rumen Fermentation Conditions

by Peter Kotsoana Montso, Caven Mguvane Mnisi, Collins Njie Ateba and Victor Mlambo

Antibiotics 2021, 10(3), 265; https://doi.org/10.3390/antibiotics10030265 - 5 Mar 2021

Cited by 5 | Viewed by 2293

Abstract

Preslaughter starvation and subacute ruminal acidosis in cattle are known to promote ruminal proliferation of atypical enteropathogenic Escherichia coli strains, thereby increasing the risk of meat and milk contamination. Using bacteriophages (henceforth called phages) to control these strains in the rumen is a potentially novel strategy. Therefore, this study evaluated the viability of phages and their efficacy in reducing E. coli O177 cells in a simulated ruminal fermentation system. Fourteen phage treatments were allocated to anaerobic serum bottles containing a grass hay substrate, buffered (pH 6.6–6.8) bovine rumen fluid, and E. coli O177 cells. The serum bottles were then incubated at 39 °C for 48 h. Phage titres quadratically increased with incubation time. Phage-induced reduction of E. coli O177 cell counts reached maximum values of 61.02–62.74% and 62.35–66.92% for single phages and phage cocktails, respectively. The highest E. coli O177 cell count reduction occurred in samples treated with vB_EcoM_366B (62.31%), vB_EcoM_3A1 (62.74%), vB_EcoMC3 (66.67%), vB_EcoMC4 (66.92%), and vB_EcoMC6 (66.42%) phages. In conclusion, lytic phages effectively reduced E. coli O177 cells under artificial rumen fermentation conditions, thus could be used as a biocontrol strategy in live cattle to reduce meat and milk contamination in abattoirs and milking parlours, respectively. Full article

(This article belongs to the Special Issue Phage Therapy to Control Pathogenic Bacteria)

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Review

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15 pages, 1429 KiB

Open AccessReview

The Role of Antibiotic Resistant A. baumannii in the Pathogenesis of Urinary Tract Infection and the Potential of Its Treatment with the Use of Bacteriophage Therapy

by Natalia Bagińska, Martyna Cieślik, Andrzej Górski and Ewa Jończyk-Matysiak

Antibiotics 2021, 10(3), 281; https://doi.org/10.3390/antibiotics10030281 - 9 Mar 2021

Cited by 30 | Viewed by 8385

Abstract

Acinetobacter baumannii are bacteria that belong to the critical priority group due to their carbapenems and third generation cephalosporins resistance, which are last-chance antibiotics. The growing multi-drug resistance and the ability of these bacteria to form biofilms makes it difficult to treat infections caused by this species, which often affects people with immunodeficiency or intensive care unit patients. In addition, most of the infections are associated with catheterization of patients. These bacteria are causative agents, inter alia, of urinary tract infections (UTI) which can cause serious medical and social problems, because of treatment difficulties as well as the possibility of recurrence and thus severely decrease patients’ quality of life. Therefore, a promising alternative to standard antibiotic therapy can be bacteriophage therapy, which will generate lower costs and will be safer for the treated patients and has real potential to be much more effective. The aim of the review is to outline the important role of drug-resistant A. baumannii in the pathogenesis of UTI and highlight the potential for fighting these infections with bacteriophage therapy. Further studies on the use of bacteriophages in the treatment of UTIs in animal models may lead to the use of bacteriophage therapy in human urinary tract infections caused by A. baumannii in the future. Full article

(This article belongs to the Special Issue Phage Therapy to Control Pathogenic Bacteria)

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Other

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12 pages, 560 KiB

Open AccessEditor’s ChoicePerspective

Basics for Improved Use of Phages for Therapy

by Philip Serwer, Elena T. Wright, Jorge De La Chapa and Cara B. Gonzales

Antibiotics 2021, 10(6), 723; https://doi.org/10.3390/antibiotics10060723 - 16 Jun 2021

Cited by 12 | Viewed by 3609

Abstract

Blood-borne therapeutic phages and phage capsids increasingly reach therapeutic targets as they acquire more persistence, i.e., become more resistant to non-targeted removal from blood. Pathogenic bacteria are targets during classical phage therapy. Metastatic tumors are potential future targets, during use of drug delivery vehicles (DDVs) that are phage derived. Phage therapy has, to date, only sometimes been successful. One cause of failure is low phage persistence. A three-step strategy for increasing persistence is to increase (1) the speed of lytic phage isolation, (2) the diversity of phages isolated, and (3) the effectiveness and speed of screening phages for high persistence. The importance of high persistence-screening is illustrated by our finding here of persistence dramatically higher for coliphage T3 than for its relative, coliphage T7, in murine blood. Coliphage T4 is more persistent, long-term than T3. Pseudomonas chlororaphis phage 201phi2-1 has relatively low persistence. These data are obtained with phages co-inoculated and separately assayed. In addition, highly persistent phage T3 undergoes dispersal to several murine organs and displays tumor tropism in epithelial tissue (xenografted human oral squamous cell carcinoma). Dispersal is an asset for phage therapy, but a liability for phage-based DDVs. We propose increased focus on phage persistence—and dispersal—screening. Full article

(This article belongs to the Special Issue Phage Therapy to Control Pathogenic Bacteria)

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