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Antibiotics
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Phage Applications from Diagnostics to Treatment of Bacterial Infections in...
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Phage Applications from Diagnostics to Treatment of Bacterial Infections in a One Health World

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

Deadline for manuscript submissions: 31 May 2025 | Viewed by 19487

Special Issue Editors

Dr. Mariagrazia Di Luca

E-Mail Website
Guest Editor
Department of Biology, University of Pisa, Via San Zeno 37, 56127 Pisa, Italy
Interests: medical biofilms; persister cells; implant-associated infections; antimicrobial resistance; antimicrobial tolerance; bacteriophages; phage therapy; antimicrobials
Special Issues, Collections and Topics in MDPI journals
Dr. Goran Vukotic

E-Mail Website
Guest Editor
Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia
Interests: bacteriophages of multi-drug resistant pathogenic bacteria; phage depolymerases; in vivo modeling phage therapy; phage DNA modification

Special Issue Information

Dear Colleagues,

In recent years, the rise of antibiotic resistance has emerged as a critical global health threat, necessitating innovative approaches to combat infectious diseases. Phage therapy, the therapeutic use of bacteriophages to target and eradicate bacterial pathogens, presents a promising avenue in this battle. This Special Issue deals with the multifaceted realm of phage therapy within the framework of One Health—a holistic approach that recognizes the interconnectedness of human, animal, and environmental health. Through a comprehensive exploration of phage therapy's role in a One Health world, this Special Issue aims to inspire innovative strategies for combating infectious diseases and safeguarding public health in an era of escalating antibiotic resistance. Exploring the intersection of microbiology, medicine, veterinary science, agriculture, and biotechnology, this Special Issue will collect articles showing the potential of phage therapy to revolutionize bacterial infection/colonization management across diverse ecosystems. From elucidating phage–host interactions to phage molecular characterizations and addressing regulatory challenges, the contributions are expected to investigate the key aspects of phage therapy research and application. In particular, this Special Issue will explore, but is not limited to, the following applications of phages: (i) therapy in human and veterinary medicine; (ii) hospital sanitization; (iii) treatment and prophylaxis in agriculture and aquaculture; (iv) wastewater plant treatment; and (v) food preservation.

Dr. Mariagrazia Di Luca
Dr. Goran Vukotic
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antibiotics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • phage therapy
  • antibiotic resistance
  • bacteriophages
  • regulatory framework
  • veterinary medicine
  • agriculture treatment
  • aquaculture

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Published Papers (8 papers)

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Research

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17 pages, 4013 KiB  
Article
A Novel Bacteriophage with the Potential to Inhibit Fusobacterium nucleatum-Induced Proliferation of Colorectal Cancer Cells
by Ho Yin Pekkle Lam, Meng-Jiun Lai, Pin-Chun Wang, Wen-Jui Wu, Li-Kuang Chen, Hsiang-Wei Fan, Chun-Chieh Tseng, Shih-Yi Peng and Kai-Chih Chang
Antibiotics 2025, 14(1), 45; https://doi.org/10.3390/antibiotics14010045 - 7 Jan 2025
Viewed by 1541
Abstract
Background: Increasing evidence shows that Fusobacterium nucleatum (F. nucleatum) largely affects colorectal cancer (CRC) growth and progression; therefore, the inhibition of intratumoral F. nucleatum may be one realistic approach to combat CRC. Although antibiotics are helpful in eliminating bacteria, the major [...] Read more.
Background: Increasing evidence shows that Fusobacterium nucleatum (F. nucleatum) largely affects colorectal cancer (CRC) growth and progression; therefore, the inhibition of intratumoral F. nucleatum may be one realistic approach to combat CRC. Although antibiotics are helpful in eliminating bacteria, the major problem remains the rise of potential antibiotic-resistant strains and antibiotic-associated adverse effects. Currently, bacteriophage therapy has gained interest because of its high selectivity to bacterial hosts and may become a realistic approach in treating bacteria-associated cancers. Methods: In this study, a new F. nucleatum bacteriophage, ØTCUFN3, was isolated and its biological characteristics were identified. In vitro and in vivo studies were performed to investigate the effect of ØTCUFN3 in combating F. nucleatum-induced CRC growth. Results: By applying ØTCUFN3 to F. nucleatum-induced CRC cell lines, p53+/+, and p53−/− isogenic HCT116 cells, our results revealed an inhibition of CRC proliferation and the expression of epithelial-to-mesenchymal transition (EMT) markers. ØTCUFN3 injection also reduced the growth of F. nucleatum-induced mouse xenografts. Conclusions: Our results demonstrated the use of F. nucleatum bacteriophage against CRC, laying the foundation for the future usage of bacteriophage in cancer treatment. Full article
(This article belongs to the Special Issue Phage Applications from Diagnostics to Treatment of Bacterial Infections in a One Health World)
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12 pages, 2080 KiB  
Article
Immunomodulatory Effect of Phage Depolymerase Dep_kpv74 with Therapeutic Potential Against K2-Hypervirulent Klebsiella pneumoniae
by Nikolay V. Volozhantsev, Maria A. Makarova, Alena S. Kartseva, Marina V. Silkina, Valentina M. Krasilnikova, Egor A. Denisenko, Alexander I. Borzilov and Victoria V. Firstova
Antibiotics 2025, 14(1), 44; https://doi.org/10.3390/antibiotics14010044 - 7 Jan 2025
Viewed by 825
Abstract
Background: The emergence of multidrug-resistant hypervirulent Klebsiella pneumoniae (hvKp) has made it difficult to treat and control infections caused by this bacterium. Previously, the therapeutic effectiveness of phage-encoded depolymerase Dep_kpv74 in a mouse model of K. pneumoniae-induced thigh soft tissue infection was [...] Read more.
Background: The emergence of multidrug-resistant hypervirulent Klebsiella pneumoniae (hvKp) has made it difficult to treat and control infections caused by this bacterium. Previously, the therapeutic effectiveness of phage-encoded depolymerase Dep_kpv74 in a mouse model of K. pneumoniae-induced thigh soft tissue infection was reported. In this study, the effect of Dep_kpv74 on blood parameters in mice, the proliferation and subpopulation composition of spleen lymphocytes, and the activity and stability of the enzyme at different pH and temperatures were further explored. Results: The stability tests showed that Dep_kpv74 remained active in the temperature range from 8 °C to 55 °C. The optimal pH value for maintaining the activity of Dep_kpv74 ranged from 5.0 to 9.0. The depolymerase was detected in the blood, spleen, and lungs of mice 10 min after intraperitoneal administration, reaching maximum activity values after 1–3 h and maintaining activity a day after administration. The introduction of Dep_kpv74 at the therapeutic dose (10 μg/mouse) or at a 10-fold higher dose did not lead to reliable changes in bloodstream cell content compared with the reference values of intact mice. The biochemical results of the studies indicated that Dep_kpv74 did not exert any toxic effects on liver and kidney functions. The results of the analysis of lymphocyte proliferative activity demonstrated that Dep_kpv74 depolymerase has a mild immunomodulatory effect. Conclusions: Thus, the results of this study provide one more confirmation that depolymerase Dep_kpv74 is a potential candidate for the treatment of infections caused by hvKp expressing K2 capsular polysaccharides. Full article
(This article belongs to the Special Issue Phage Applications from Diagnostics to Treatment of Bacterial Infections in a One Health World)
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14 pages, 5729 KiB  
Article
Standardization of the Agar Plate Method for Bacteriophage Production
by Su Jin Jo, Young Min Lee, Kevin Cho, Seon Young Park, Hyemin Kwon, Sib Sankar Giri, Sung Bin Lee, Won Joon Jung, Jae Hong Park, Mae Hyun Hwang, Da Sol Park, Eun Jae Park, Sang Wha Kim, Jin Woo Jun, Sang Guen Kim, Ji Hyung Kim and Se Chang Park
Antibiotics 2025, 14(1), 2; https://doi.org/10.3390/antibiotics14010002 - 24 Dec 2024
Cited by 1 | Viewed by 2014
Abstract
The growing threat of antimicrobial resistance (AMR), exacerbated by the COVID-19 pandemic, highlights the urgent need for alternative treatments such as bacteriophage (phage) therapy. Phage therapy offers a targeted approach to combat bacterial infections, particularly those resistant to conventional antibiotics. This study aimed [...] Read more.
The growing threat of antimicrobial resistance (AMR), exacerbated by the COVID-19 pandemic, highlights the urgent need for alternative treatments such as bacteriophage (phage) therapy. Phage therapy offers a targeted approach to combat bacterial infections, particularly those resistant to conventional antibiotics. This study aimed to standardize an agar plate method for high-mix, low-volume phage production, suitable for personalized phage therapy. Plaque assays were conducted with the double-layer agar method, and plaque sizes were precisely measured using image analysis tools. Regression models developed with Minitab software established correlations between plaque size and phage production, optimizing production while minimizing resistance development. The resulting Plaque Size Calculation (PSC) model accurately correlated plaque size with inoculum concentration and phage yield, establishing specific plaque-forming unit (PFU) thresholds for optimal production. Using phages targeting pathogens such as Escherichia, Salmonella, Staphylococcus, Pseudomonas, Chryseobacterium, Vibrio, Erwinia, and Aeromonas confirmed the model’s accuracy across various conditions. The model’s validation showed a strong inverse correlation between plaque size and minimum-lawn cell clearing PFUs (MCPs; R² = 98.91%) and identified an optimal inoculum density that maximizes yield while minimizing the evolution of resistant mutants. These results highlight that the PSC model offers a standardized and scalable method for efficient phage production, which is crucial for personalized therapy and AMR management. Furthermore, its adaptability across different conditions and phages positions it as a potential standard tool for rapid and precise phage screening and propagation in both clinical and industrial settings. Full article
(This article belongs to the Special Issue Phage Applications from Diagnostics to Treatment of Bacterial Infections in a One Health World)
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19 pages, 5938 KiB  
Article
Isolation and Characterization of a Novel Escherichia Bacteriophage with Potential to Control Multidrug-Resistant Avian Pathogenic Escherichia coli and Biofilms
by Phitchayapak Wintachai, Fahsai Thaion, Martha R. J. Clokie and Thotsapol Thomrongsuwannakij
Antibiotics 2024, 13(11), 1083; https://doi.org/10.3390/antibiotics13111083 - 13 Nov 2024
Viewed by 1891
Abstract
Background/Objectives: Avian pathogenic Escherichia coli (APEC) infection is a significant problem for the global chicken industry, as it decreases animal welfare and is associated with substantial economic losses. Traditionally, APEC infections have been controlled through the use of antibiotics, which has led to [...] Read more.
Background/Objectives: Avian pathogenic Escherichia coli (APEC) infection is a significant problem for the global chicken industry, as it decreases animal welfare and is associated with substantial economic losses. Traditionally, APEC infections have been controlled through the use of antibiotics, which has led to an increased prevalence of antibiotic-resistant E. coli. Therefore, developing alternative treatments for APEC infection is crucial. Methods: In this study, an Escherichia phage specific to multidrug-resistant (MDR) APEC, designated as phage vB_EcoP_PW8 (phage vECPW8), was isolated. The morphology, phage adsorption to host cells, one-step growth curve, thermal stability, pH stability, whole-genome sequencing, antibacterial ability, and antibiofilm efficacy of phage vECPW8 were evaluated. Results: The results demonstrated that phage vECPW8 has a Podoviridae morphology and is effective at lysing bacteria. Phage vECPW8 exhibited a high absorption rate to bacterial cells (more than 85% within 10 min) and had a latent period of 20 min, with a burst size of 143 plaque-forming units per cell. Additionally, phage vECPW8 showed good temperature and pH stability. The phage displayed strong antibacterial activity in vitro, and its efficacy in controlling bacteria was confirmed through scanning electron microscopy. Whole-genome sequencing revealed that the phage has a linear genome with 69,579 base pairs. The genome analysis supported the safety of the phage, as no toxin, virulence, or resistance-related genes were detected. Phage vECPW8 was identified as a novel lytic phage in the Gamaleyavirus genus and Schitoviridae family. The phage also demonstrated antibiofilm efficacy by reducing and preventing biofilm formation, as evidenced by biofilm biomass and bacterial cell viability measurements. Conclusions: These results indicate that phage vECPW8 is a promising candidate for the effective treatment of MDR APEC infections in poultry. Full article
(This article belongs to the Special Issue Phage Applications from Diagnostics to Treatment of Bacterial Infections in a One Health World)
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20 pages, 3728 KiB  
Article
Isolation and Characterization of a Novel Jumbo Phage HPP-Temi Infecting Pseudomonas aeruginosa Pa9 and Increasing Host Sensitivity to Ciprofloxacin
by Olufunke Olufunmilola Olorundare, Nikita Zrelovs, Dennis Kabantiyok, Karina Svanberga, Juris Jansons, Andris Kazaks, Godwin Ojonugwa Agada, Chibuzor Gerald Agu, Oluwatoyin Ruth Morenikeji, Ogundeji Alice Oluwapelumi, Thomas Dung and Shedrach Benjamin Pewan
Antibiotics 2024, 13(11), 1006; https://doi.org/10.3390/antibiotics13111006 - 25 Oct 2024
Cited by 1 | Viewed by 6550
Abstract
Pseudomonas aeruginosa is a bacteria responsible for many hospital-acquired infections. Phages are promising alternatives for treating P. aeruginosa infections, which are often intrinsically resistant. The combination of phage and antibiotics in clearing bacterial infection holds promise due to increasing reports of enhanced effectiveness [...] Read more.
Pseudomonas aeruginosa is a bacteria responsible for many hospital-acquired infections. Phages are promising alternatives for treating P. aeruginosa infections, which are often intrinsically resistant. The combination of phage and antibiotics in clearing bacterial infection holds promise due to increasing reports of enhanced effectiveness when both are used together. The aim of the study is to isolate and characterize a novel P. aeruginosa phage and determine its effectiveness in in vitro combination with antibiotics in controlling P. aeruginosa. In this study, a novel jumbo myophage HPP-Temi infecting P. aeruginosa Pa9 (PP334386) was isolated from household sewage. Electron micrographs of the phage were obtained to determine the morphological features of HPP-Temi virions. Complete genome analysis and a combination of Pseudomonas phage HPP-Temi with antibiotics were examined. The phage HPP-Temi was able to productively infect P. aeruginosa ATCC 9027 but was unable to infect a closely related genus. The phage was stable at 4–37 °C, 0.5% NaCl, and pH 8 for at least one hour. The HPP-Temi genome is a 302,719-bp-long dsDNA molecule with a GC content of 46.46%. The genome was predicted to have 436 ORFs and 7 tRNA genes. No virulence factor-related genes, antimicrobial resistance, or temperate lifestyle-associated genes were found in the phage HPP-Temi genome. Phage HPP-Temi is most closely related to the known or tentative representatives of the Pawinskivirus genus and can be proposed as a representative for the creation of a novel phage species in that genus. The phage and antibiotics (Ciprofloxacin) combination at varying phage titers (103, 106, 109) were used against P. aeruginosa Pa9 (PP334386) at 3.0 × 108 CFU/mL, which was carried out in triplicate. The result showed that combining antibiotics with phage significantly reduced the bacteria count at 103 and 106 titers, while no growth was observed at 109 PFU/mL. This suggests that the effect of phage HPP-Temi in combination with antibiotics is a potential and promising agent for the control of P. aeruginosa infections. Full article
(This article belongs to the Special Issue Phage Applications from Diagnostics to Treatment of Bacterial Infections in a One Health World)
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21 pages, 5445 KiB  
Article
Characterization of Two Novel Endolysins from Bacteriophage PEF1 and Evaluation of Their Combined Effects on the Control of Enterococcus faecalis Planktonic and Biofilm Cells
by Chen Wang, Junxin Zhao, Yunzhi Lin, Su Zar Chi Lwin, Mohamed El-Telbany, Yoshimitsu Masuda, Ken-ichi Honjoh and Takahisa Miyamoto
Antibiotics 2024, 13(9), 884; https://doi.org/10.3390/antibiotics13090884 - 13 Sep 2024
Viewed by 1711
Abstract
Endolysin, a bacteriophage-derived lytic enzyme, has emerged as a promising alternative antimicrobial agent against rising multidrug-resistant bacterial infections. Two novel endolysins LysPEF1-1 and LysPEF1-2 derived from Enterococcus phage PEF1 were cloned and overexpressed in Escherichia coli to test their antimicrobial efficacy against multidrug-resistant [...] Read more.
Endolysin, a bacteriophage-derived lytic enzyme, has emerged as a promising alternative antimicrobial agent against rising multidrug-resistant bacterial infections. Two novel endolysins LysPEF1-1 and LysPEF1-2 derived from Enterococcus phage PEF1 were cloned and overexpressed in Escherichia coli to test their antimicrobial efficacy against multidrug-resistant E. faecalis strains and their biofilms. LysPEF1-1 comprises an enzymatically active domain and a cell-wall-binding domain originating from the NLPC-P60 and SH3 superfamilies, while LysPEF1-2 contains a putative peptidoglycan recognition domain that belongs to the PGRP superfamily. LysPEF1-1 was active against 89.86% (62/69) of Enterococcus spp. tested, displaying a wider antibacterial spectrum than phage PEF1. Moreover, two endolysins demonstrated lytic activity against additional gram-positive and gram-negative species pretreated with chloroform. LysPEF1-1 showed higher activity against multidrug-resistant E. faecalis strain E5 than LysPEF1-2. The combination of two endolysins effectively reduced planktonic cells of E5 in broth and was more efficient at inhibiting biofilm formation and removing biofilm cells of E. faecalis JCM 7783T than used individually. Especially at 4 °C, they reduced viable biofilm cells by 4.5 log after 2 h of treatment on glass slide surfaces. The results suggest that two novel endolysins could be alternative antimicrobial agents for controlling E. faecalis infections. Full article
(This article belongs to the Special Issue Phage Applications from Diagnostics to Treatment of Bacterial Infections in a One Health World)
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19 pages, 3718 KiB  
Article
Isolation and Characterization of Two Novel Genera of Jumbo Bacteriophages Infecting Xanthomonas vesicatoria Isolated from Agricultural Regions in Mexico
by Claudia Villicaña, Lucía M. Rubí-Rangel, Luis Amarillas, Luis Alberto Lightbourn-Rojas, José Armando Carrillo-Fasio and Josefina León-Félix
Antibiotics 2024, 13(7), 651; https://doi.org/10.3390/antibiotics13070651 - 15 Jul 2024
Cited by 1 | Viewed by 1702
Abstract
Bacterial spot is a serious disease caused by several species of Xanthomonas affecting pepper and tomato production worldwide. Since the strategies employed for disease management have been inefficient and pose a threat for environmental and human health, the development of alternative methods is [...] Read more.
Bacterial spot is a serious disease caused by several species of Xanthomonas affecting pepper and tomato production worldwide. Since the strategies employed for disease management have been inefficient and pose a threat for environmental and human health, the development of alternative methods is gaining relevance. The aim of this study is to isolate and characterize lytic phages against Xanthomonas pathogens. Here, we isolate two jumbo phages, named XaC1 and XbC2, from water obtained from agricultural irrigation channels by the enrichment technique using X. vesicatoria as a host. We determined that both phages were specific for inducing the lysis of X. vesicatoria strains, but not of other xanthomonads. The XaC1 and XbC2 phages showed a myovirus morphology and were classified as jumbo phages due to their genomes being larger than 200 kb. Phylogenetic and comparative analysis suggests that XaC1 and XbC2 represent both different and novel genera of phages, where XaC1 possesses a low similarity to other phage genomes reported before. Finally, XaC1 and XbC2 exhibited thermal stability up to 45 °C and pH stability from 5 to 9. All these results indicate that the isolated phages are promising candidates for the development of formulations against bacterial spot, although further characterization is required. Full article
(This article belongs to the Special Issue Phage Applications from Diagnostics to Treatment of Bacterial Infections in a One Health World)
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Review

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17 pages, 1771 KiB  
Review
Mycobacteriophages and Their Applications
by Andrea Bonacorsi, Caterina Ferretti, Mariagrazia Di Luca and Laura Rindi
Antibiotics 2024, 13(10), 926; https://doi.org/10.3390/antibiotics13100926 - 27 Sep 2024
Cited by 1 | Viewed by 2345
Abstract
Mycobacterial infections caused by tuberculous and non-tuberculous strains pose significant treatment challenges, especially among immunocompromised patients. Conventional antibiotic therapies often fail due to bacterial resistance, highlighting the need for alternative therapeutic strategies. Mycobacteriophages are emerging as promising candidates for the treatment of mycobacteria. [...] Read more.
Mycobacterial infections caused by tuberculous and non-tuberculous strains pose significant treatment challenges, especially among immunocompromised patients. Conventional antibiotic therapies often fail due to bacterial resistance, highlighting the need for alternative therapeutic strategies. Mycobacteriophages are emerging as promising candidates for the treatment of mycobacteria. This review comprehensively explores phage isolation, characterization, and clinical applications. Despite the need for more extensive in vitro and in vivo studies, existing evidence shows their efficacy against both sensitive and antibiotic-resistant mycobacterial strains, even under disease-mimicking conditions, particularly when used in cocktails to minimize resistance development. Mycobacteriophages can be engineered and evolved to overcome limitations associated with lysogeny and narrow host range. Furthermore, they exhibit activity in ex vivo and in vivo infection models, successfully targeting mycobacteria residing within macrophages. Delivery methods such as bacterial and liposomal vectors facilitate their entry into human cells. Considering the potential for phage-treatment-induced bacterial resistance, as described in this review, the combination of mycobacteriophages with antibiotics shows efficacy in countering mycobacterial growth, both in the laboratory setting and in animal models. Interestingly, phage-encoded products can potentiate the activity of relevant antibiotics. Finally, the application of phages in different compassionate cases is reported. The positive outcomes indicate that phage therapy represents a promising solution for the treatment of antibiotic-resistant mycobacteria. Full article
(This article belongs to the Special Issue Phage Applications from Diagnostics to Treatment of Bacterial Infections in a One Health World)
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