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Antibiotics
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Benefits of Bacteriophages to Combat Antibiotic-Resistant Bacteria
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Benefits of Bacteriophages to Combat Antibiotic-Resistant Bacteria

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

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 51502

Special Issue Editor

Dr. Pilar García Suárez

E-Mail Website
Guest Editor
Instituto de Productos Lácteos de Asturias (IPLA-CSIC), Paseo Río Linares, sn, 33300 Villaviciosa, Asturias, Spain
Interests: bacteriophages; endolysins; phage therapy; biocontrol; Staphylococcus aureus; biofilms
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Bacteriophages are important players in microbial communities, modulating bacterial growth and evolution. They also contribute to pathogenicity by providing virulence factors and antibiotic resistance genes, which can be further spread in the bacterial population. Indeed, phages might be vehicles for horizontal exchange of genetic material by transduction, in some cases resulting in bacteria with increased resistance to therapeutic drugs. Recently, in Western countries, bacteriophages have been proposed as an attractive alternative to antibiotics (phage therapy) for the treatment of bacterial infections. However, the risk that a massive use of bacteriophages may contribute to the development of antibiotic resistance through the transmission of genetic material is an as of yet unsolved problem. Moreover, although the real contribution of therapeutic phages to the diffusion of resistance has not been precisely defined, it seems clear that phages are important reservoirs of resistance genes. Despite these drawbacks, progress in new technologies, such as genome editing and synthetic biology, offers a wide variety of possibilities to generate phages with adequate properties for prophylactic and therapeutic applications. Some examples of strategies to improve phages intended for phage therapy include deletion of undesirable genes, expanding phage host range or disrupting some capsid epitopes to eliminate immune responses. Our possibilities can go even further by using phages that deliver CRISPR-Cas systems and sensitize bacteria to antibiotics, thereby facilitating the replacement of antibiotic-resistant pathogens with their sensitive counterparts. The main subject of this Special Issue includes any bacteriophage-based approach to prevent or control antibiotic resistant bacteria, especially human pathogenic bacteria. The issue welcomes various submission types, such as original research papers, short communications, reviews, case reports, and perspectives. Potential topics include phage therapy (human and veterinary medicine), prophylactic applications of phages (development of vaccine platforms), and the use of phage genome engineering or CRISPR-Cas-based phage engineering to obtain phages suitable for reducing antibiotic-resistant bacteria.

Dr. Pilar García Suárez
Guest Editor

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

  • Antibiotic resistance
  • bacteriophages
  • phage therapy
  • antimicrobials
  • vaccines
  • CRISPR-Cas
  • synthetic biology
  • genome engineering

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Published Papers (9 papers)

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Research

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19 pages, 3645 KiB  
Article
Natural Bred ε2-Phages Have an Improved Host Range and Virulence against Uropathogenic Escherichia coli over Their Ancestor Phages
by Maria Loose, David Sáez Moreno, Michele Mutti, Eva Hitzenhammer, Zehra Visram, David Dippel, Susanne Schertler, Lenka Podpera Tišáková, Johannes Wittmann, Lorenzo Corsini and Florian Wagenlehner
Antibiotics 2021, 10(11), 1337; https://doi.org/10.3390/antibiotics10111337 - 1 Nov 2021
Cited by 7 | Viewed by 3319
Abstract
Alternative treatments for Escherichia coli infections are urgently needed, and phage therapy is a promising option where antibiotics fail, especially for urinary tract infections (UTI). We used wastewater-isolated phages to test their lytic activity against a panel of 47 E. coli strains reflecting [...] Read more.
Alternative treatments for Escherichia coli infections are urgently needed, and phage therapy is a promising option where antibiotics fail, especially for urinary tract infections (UTI). We used wastewater-isolated phages to test their lytic activity against a panel of 47 E. coli strains reflecting the diversity of strains found in UTI, including sequence type 131, 73 and 69. The plaquing host range (PHR) was between 13 and 63%. In contrast, the kinetic host range (KHR), describing the percentage of strains for which growth in suspension was suppressed for 24 h, was between 0% and 19%, substantially lower than the PHR. To improve the phage host range and their efficacy, we bred the phages by mixing and propagating cocktails on a subset of E. coli strains. The bred phages, which we termed evolution-squared ε2-phages, of a mixture of Myoviridae have KHRs up to 23% broader compared to their ancestors. Furthermore, using constant phage concentrations, Myoviridae ε2-phages suppressed the growth of higher bacterial inocula than their ancestors did. Thus, the ε2-phages were more virulent compared to their ancestors. Analysis of the genetic sequences of the ε2-phages with the broadest host range reveals that they are mosaic intercrossings of 2–3 ancestor phages. The recombination sites are distributed over the whole length of the genome. All ε2-phages are devoid of genes conferring lysogeny, antibiotic resistance, or virulence. Overall, this study shows that ε2-phages are remarkably more suitable than the wild-type phages for phage therapy. Full article
(This article belongs to the Special Issue Benefits of Bacteriophages to Combat Antibiotic-Resistant Bacteria)
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14 pages, 2544 KiB  
Article
Targeting Biofilm of MDR Providencia stuartii by Phages Using a Catheter Model
by Chani Rakov, Shira Ben Porat, Sivan Alkalay-Oren, Ortal Yerushalmy, Mohanad Abdalrhman, Niv Gronovich, Lina Huang, David Pride, Shunit Coppenhagen-Glazer, Ran Nir-Paz and Ronen Hazan
Antibiotics 2021, 10(4), 375; https://doi.org/10.3390/antibiotics10040375 - 2 Apr 2021
Cited by 16 | Viewed by 3642
Abstract
Providencia spp. are emerging pathogens mainly in nosocomial infections. Providencia stuartii in particular is involved in urinary tract infections and contributes significantly to the high incidence of biofilm-formation in catheterized patients. Furthermore, recent reports suggested a role for multiple drug resistant (MDR) P. [...] Read more.
Providencia spp. are emerging pathogens mainly in nosocomial infections. Providencia stuartii in particular is involved in urinary tract infections and contributes significantly to the high incidence of biofilm-formation in catheterized patients. Furthermore, recent reports suggested a role for multiple drug resistant (MDR) P. stuartii in hospital-associated outbreaks which leads to excessive complications resulting in challenging treatments. Phage therapy is currently one of the most promising solutions to combat antibiotic-resistant infections. However, the number of available phages targeting Providencia spp. is extremely limited, restricting the use of phage therapy in such cases. In the present study, we describe the isolation and characterization of 17 lytic and temperate bacteriophages targeting clinical isolates of Providencia spp. as part of the Israeli Phage Bank (IPB). These phages, isolated from sewage samples, were evaluated for host range activity and effectively eradicated 95% of the tested bacterial strains isolated from different geographic locations and displaying a wide range of antibiotic resistance. Their lytic activity is demonstrated on agar plates, planktonic cultures, and biofilm formed in a catheter model. The results suggest that these bacteriophages can potentially be used for treatment of antibiotic-resistant Providencia spp. infections in general and of urinary tract infections in particular. Full article
(This article belongs to the Special Issue Benefits of Bacteriophages to Combat Antibiotic-Resistant Bacteria)
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14 pages, 969 KiB  
Article
λ Recombineering Used to Engineer the Genome of Phage T7
by Jordan D. Jensen, Adam R. Parks, Sankar Adhya, Alison J. Rattray and Donald L. Court
Antibiotics 2020, 9(11), 805; https://doi.org/10.3390/antibiotics9110805 - 13 Nov 2020
Cited by 15 | Viewed by 3879
Abstract
Bacteriophage T7 and T7-like bacteriophages are valuable genetic models for lytic phage biology that have heretofore been intractable with in vivo genetic engineering methods. This manuscript describes that the presence of λ Red recombination proteins makes in vivo recombineering of T7 possible, so [...] Read more.
Bacteriophage T7 and T7-like bacteriophages are valuable genetic models for lytic phage biology that have heretofore been intractable with in vivo genetic engineering methods. This manuscript describes that the presence of λ Red recombination proteins makes in vivo recombineering of T7 possible, so that single base changes and whole gene replacements on the T7 genome can be made. Red recombination functions also increase the efficiency of T7 genome DNA transfection of cells by ~100-fold. Likewise, Red function enables two other T7-like bacteriophages that do not normally propagate in E. coli to be recovered following genome transfection. These results constitute major technical advances in the speed and efficiency of bacteriophage T7 engineering and will aid in the rapid development of new phage variants for a variety of applications. Full article
(This article belongs to the Special Issue Benefits of Bacteriophages to Combat Antibiotic-Resistant Bacteria)
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16 pages, 2374 KiB  
Article
Characterization and Therapeutic Potential of Bacteriophage-Encoded Polysaccharide Depolymerases with β Galactosidase Activity against Klebsiella pneumoniae K57 Capsular Type
by Nikolay V. Volozhantsev, Anna M. Shpirt, Alexander I. Borzilov, Ekaterina V. Komisarova, Valentina M. Krasilnikova, Alexander S. Shashkov, Vladimir V. Verevkin and Yuriy A. Knirel
Antibiotics 2020, 9(11), 732; https://doi.org/10.3390/antibiotics9110732 - 25 Oct 2020
Cited by 26 | Viewed by 3716
Abstract
Bacteriophages and phage enzymes are considered as possible alternatives to antibiotics in the treatment of infections caused by antibiotic-resistant bacteria. Due to the ability to cleave the capsular polysaccharides (CPS), one of the main virulence factors of Klebsiella pneumoniae, phage depolymerases, has [...] Read more.
Bacteriophages and phage enzymes are considered as possible alternatives to antibiotics in the treatment of infections caused by antibiotic-resistant bacteria. Due to the ability to cleave the capsular polysaccharides (CPS), one of the main virulence factors of Klebsiella pneumoniae, phage depolymerases, has potential in the treatment of K. pneumoniae infections. Here, we characterized in vivo two novel phage-encoded polysaccharide depolymerases as therapeutics against clinical isolates of K. pneumoniae. The depolymerases Dep_kpv79 and Dep_kpv767 encoded by Klebsiella phages KpV79 (Myoviridae; Jedunavirus) and KpV767 (Autographiviridae, Studiervirinae, Przondovirus), respectively, were identified as specific β-galactosidases that cleave the K. pneumoniae K57 type CPS by the hydrolytic mechanism. They were found to be highly effective at combating sepsis and hip infection caused by K. pneumoniae in lethal mouse models. Here, 80–100% of animals were protected against death by a single dose (e.g., 50 μg/mouse) of the enzyme injected 0.5 h after infection by K. pneumoniae strains of the K57 capsular type. The therapeutic effect of the depolymerases is because they strip the capsule and expose the underlying bacterium to the immune attack such as complement-mediated killing. These data provide one more confirmation that phage polysaccharide depolymerases represent a promising tool for antimicrobial therapy. Full article
(This article belongs to the Special Issue Benefits of Bacteriophages to Combat Antibiotic-Resistant Bacteria)
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Review

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22 pages, 1062 KiB  
Review
Potential for Phages in the Treatment of Bacterial Sexually Transmitted Infections
by Kathryn Cater, Ryszard Międzybrodzki, Vera Morozova, Sławomir Letkiewicz, Marzanna Łusiak-Szelachowska, Justyna Rękas, Beata Weber-Dąbrowska and Andrzej Górski
Antibiotics 2021, 10(9), 1030; https://doi.org/10.3390/antibiotics10091030 - 24 Aug 2021
Cited by 8 | Viewed by 5316
Abstract
Bacterial sexually transmitted infections (BSTIs) are becoming increasingly significant with the approach of a post-antibiotic era. While treatment options dwindle, the transmission of many notable BSTIs, including Neisseria gonorrhoeae, Chlamydia trachomatis, and Treponema pallidum, continues to increase. Bacteriophage therapy has been [...] Read more.
Bacterial sexually transmitted infections (BSTIs) are becoming increasingly significant with the approach of a post-antibiotic era. While treatment options dwindle, the transmission of many notable BSTIs, including Neisseria gonorrhoeae, Chlamydia trachomatis, and Treponema pallidum, continues to increase. Bacteriophage therapy has been utilized in Poland, Russia and Georgia in the treatment of bacterial illnesses, but not in the treatment of bacterial sexually transmitted infections. With the ever-increasing likelihood of antibiotic resistance prevailing and the continuous transmission of BSTIs, alternative treatments must be explored. This paper discusses the potentiality and practicality of phage therapy to treat BSTIs, including Neisseria gonorrhoeae, Chlamydia trachomatis, Treponema pallidum, Streptococcus agalactiae, Haemophilus ducreyi, Calymmatobacterium granulomatis, Mycoplasma genitalium, Ureaplasma parvum, Ureaplasma urealyticum, Shigella flexneri and Shigella sonnei. The challenges associated with the potential for phage in treatments vary for each bacterial sexually transmitted infection. Phage availability, bacterial structure and bacterial growth may impact the potential success of future phage treatments. Additional research is needed before BSTIs can be successfully clinically treated with phage therapy or phage-derived enzymes. Full article
(This article belongs to the Special Issue Benefits of Bacteriophages to Combat Antibiotic-Resistant Bacteria)
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15 pages, 1235 KiB  
Review
Gram-Positive Pneumonia: Possibilities Offered by Phage Therapy
by Lucía Fernández, María Dolores Cima-Cabal, Ana Catarina Duarte, Ana Rodríguez, María del Mar García-Suárez and Pilar García
Antibiotics 2021, 10(8), 1000; https://doi.org/10.3390/antibiotics10081000 - 18 Aug 2021
Cited by 6 | Viewed by 10243
Abstract
Pneumonia is an acute pulmonary infection whose high hospitalization and mortality rates can, on occasion, bring healthcare systems to the brink of collapse. Both viral and bacterial pneumonia are uncovering many gaps in our understanding of host–pathogen interactions, and are testing the effectiveness [...] Read more.
Pneumonia is an acute pulmonary infection whose high hospitalization and mortality rates can, on occasion, bring healthcare systems to the brink of collapse. Both viral and bacterial pneumonia are uncovering many gaps in our understanding of host–pathogen interactions, and are testing the effectiveness of the currently available antimicrobial strategies. In the case of bacterial pneumonia, the main challenge is antibiotic resistance, which is only expected to increase during the current pandemic due to the widespread use of antibiotics to prevent secondary infections in COVID-19 patients. As a result, alternative therapeutics will be necessary to keep this disease under control. This review evaluates the advantages of phage therapy to treat lung bacterial infections, in particular those caused by the Gram-positive bacteria Streptococcus pneumoniae and Staphylococcus aureus, while also highlighting the regulatory impediments that hamper its clinical use and the difficulties associated with phage research. Full article
(This article belongs to the Special Issue Benefits of Bacteriophages to Combat Antibiotic-Resistant Bacteria)
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15 pages, 920 KiB  
Review
Phages in Food Industry Biocontrol and Bioremediation
by Pablo Cristobal-Cueto, Alberto García-Quintanilla, Jaime Esteban and Meritxell García-Quintanilla
Antibiotics 2021, 10(7), 786; https://doi.org/10.3390/antibiotics10070786 - 28 Jun 2021
Cited by 42 | Viewed by 8002
Abstract
Bacteriophages are ubiquitous in nature and their use is a current promising alternative in biological control. Multidrug resistant (MDR) bacterial strains are present in the livestock industry and phages are attractive candidates to eliminate them and their biofilms. This alternative therapy also reduces [...] Read more.
Bacteriophages are ubiquitous in nature and their use is a current promising alternative in biological control. Multidrug resistant (MDR) bacterial strains are present in the livestock industry and phages are attractive candidates to eliminate them and their biofilms. This alternative therapy also reduces the non-desirable effects produced by chemicals on food. The World Health Organization (WHO) estimates that around 420,000 people die due to a foodborne illness annually, suggesting that an improvement in food biocontrol is desirable. This review summarizes relevant studies of phage use in biocontrol focusing on treatments in live animals, plants, surfaces, foods, wastewaters and bioremediation. Full article
(This article belongs to the Special Issue Benefits of Bacteriophages to Combat Antibiotic-Resistant Bacteria)
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23 pages, 396 KiB  
Review
Advances in Bacteriophage Therapy against Relevant MultiDrug-Resistant Pathogens
by Antonio Broncano-Lavado, Guillermo Santamaría-Corral, Jaime Esteban and Meritxell García-Quintanilla
Antibiotics 2021, 10(6), 672; https://doi.org/10.3390/antibiotics10060672 - 4 Jun 2021
Cited by 36 | Viewed by 6935
Abstract
The increase of multiresistance in bacteria and the shortage of new antibiotics in the market is becoming a major public health concern. The World Health Organization (WHO) has declared critical priority to develop new antimicrobials against three types of bacteria: carbapenem-resistant A. baumannii [...] Read more.
The increase of multiresistance in bacteria and the shortage of new antibiotics in the market is becoming a major public health concern. The World Health Organization (WHO) has declared critical priority to develop new antimicrobials against three types of bacteria: carbapenem-resistant A. baumannii, carbapenem-resistant P. aeruginosa and carbapenem-resistant and ESBL-producing Enterobacteriaceae. Phage therapy is a promising alternative therapy with renewed research in Western countries. This field includes studies in vitro, in vivo, clinical trials and clinical cases of patients receiving phages as the last resource after failure of standard treatments due to multidrug resistance. Importantly, this alternative treatment has been shown to be more effective when administered in combination with antibiotics, including infections with biofilm formation. This review summarizes the most recent studies of this strategy in animal models, case reports and clinical trials to deal with infections caused by resistant A. baumannii, K. pneumoniae, E. coli, and P. aeruginosa strains, as well as discusses the main limitations of phage therapy. Full article
(This article belongs to the Special Issue Benefits of Bacteriophages to Combat Antibiotic-Resistant Bacteria)
8 pages, 833 KiB  
Review
Use of Bacteriophage Amended with CRISPR-Cas Systems to Combat Antimicrobial Resistance in the Bacterial Foodborne Pathogen Listeria monocytogenes
by Cameron Parsons, Phillip Brown and Sophia Kathariou
Antibiotics 2021, 10(3), 308; https://doi.org/10.3390/antibiotics10030308 - 17 Mar 2021
Cited by 10 | Viewed by 3850
Abstract
Listeria monocytogenes is a bacterial foodborne pathogen and the causative agent of the disease listeriosis, which though uncommon can result in severe symptoms such as meningitis, septicemia, stillbirths, and abortions and has a high case fatality rate. This pathogen can infect humans and [...] Read more.
Listeria monocytogenes is a bacterial foodborne pathogen and the causative agent of the disease listeriosis, which though uncommon can result in severe symptoms such as meningitis, septicemia, stillbirths, and abortions and has a high case fatality rate. This pathogen can infect humans and other animals, resulting in massive health and economic impacts in the United States and globally. Listeriosis is treated with antimicrobials, typically a combination of a beta-lactam and an aminoglycoside, and L. monocytogenes has remained largely susceptible to the drugs of choice. However, there are several reports of antimicrobial resistance (AMR) in both L. monocytogenes and other Listeria species. Given the dire health outcomes associated with listeriosis, the prospect of antimicrobial-resistant L. monocytogenes is highly problematic for human and animal health. Developing effective tools for the control and elimination of L. monocytogenes, including strains with antimicrobial resistance, is of the utmost importance to prevent further dissemination of AMR in this pathogen. One tool that has shown great promise in combating antibiotic-resistant pathogens is the use of bacteriophages (phages), which are natural bacterial predators and horizontal gene transfer agents. Although native phages can be effective at killing antibiotic-resistant pathogens, limited host ranges and evolved resistance to phages can compromise their use in the efforts to mitigate the global AMR challenge. However, recent advances can allow the use of CRISPR-Cas (clustered regularly interspaced short palindromic repeats-CRISPR-associated proteins) to selectively target pathogens and their AMR determinants. Employment of CRISPR-Cas systems for phage amendment can overcome previous limitations in using phages as biocontrol and allow for the effective control of L. monocytogenes and its AMR determinants. Full article
(This article belongs to the Special Issue Benefits of Bacteriophages to Combat Antibiotic-Resistant Bacteria)
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