Bacteriophages and Other Alternative Antimicrobials to Combat Multidrug Resistance

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

Deadline for manuscript submissions: closed (30 June 2024) | Viewed by 16946

Special Issue Editors


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Guest Editor
Wound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA
Interests: bacteriophage biology and bacteriophage therapy

E-Mail
Guest Editor
Wound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA
Interests: bacteriophage molecular biology and bacteriophage therapy

Special Issue Information

Dear Colleagues,

The global spread of antibiotic resistance in pathogenic bacteria has become an accelerating public health disaster that calls for the development of novel therapeutic approaches. These new antibacterial agents include bacteriophages, small molecule antibiotics, monoclonal antibodies, antivirulence drugs, antimicrobial peptides, bacteriocins, and predatory bacteria. Some of these novel drugs have shown significant efficacy in laboratory animals and in humans. There are publications that describe multiple positive outcomes in patients with different severe multidrug-resistant infections by compassionate use as well as some successful clinical trials for evaluating new antibacterials. However, much work remains!

This Special Issue is focused on isolation, synthesis, engineering, characterization, preclinical testing and clinical use of any novel antibacterials that are alternatives to classical antibiotics. Articles covering comparisons and combinations of new drugs and standard-of-care antibiotics are also welcome. Additional topics of interest will include safety, stability and immunogenicity of novel drugs, improved formulations, manufacturing, storage, delivery, regulatory aspects, and the development of bacterial resistance and ways to overcome it. Both original papers and review articles will be considered for publication in this Special Issue of Antibiotics.

Dr. Andrey A. Filippov
Dr. Mikeljon P. Nikolich
Guest Editors

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Keywords

  • multidrug resistance
  • alternative antibacterials
  • bacteriophage therapy
  • phage-antibiotic synergy
  • phage lysins
  • small molecule drugs
  • monoclonal antibodies
  • antivirulence drugs
  • pharmacokinetics and pharmacodynamics
  • resistance to novel drugs

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Published Papers (8 papers)

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Research

19 pages, 2249 KiB  
Article
Safety and Tolerability of ShigActive™, a Shigella spp. Targeting Bacteriophage Preparation, in a Phase 1 Randomized, Double-Blind, Controlled Clinical Trial
by Wilbur H. Chen, Joelle Woolston, Silvia Grant-Beurmann, Courtney K. Robinson, Garima Bansal, Joseph Nkeze, Jasnehta Permala-Booth, Claire M. Fraser, Sharon M. Tennant, Mallory C. Shriver, Marcela F. Pasetti, Yuanyuan Liang, Karen L. Kotloff, Alexander Sulakvelidze and Jennifer A. Schwartz
Antibiotics 2024, 13(9), 858; https://doi.org/10.3390/antibiotics13090858 - 7 Sep 2024
Viewed by 1533
Abstract
Bacterial diseases of the gastrointestinal (GI) tract continue to be a major worldwide cause of human morbidity and mortality. Among various enteric pathogens, Shigella spp. are some of the most common and deadly bacterial pathogens. They are responsible for ~125 million worldwide cases [...] Read more.
Bacterial diseases of the gastrointestinal (GI) tract continue to be a major worldwide cause of human morbidity and mortality. Among various enteric pathogens, Shigella spp. are some of the most common and deadly bacterial pathogens. They are responsible for ~125 million worldwide cases of shigellosis, and ~14,000 deaths annually, the majority in children under the age of 5 and occurring in developing countries. Preventing and treating shigellosis with conventional drugs (e.g., vaccines and antibiotics) has proven to be very difficult. Here, we assessed the safety and tolerability of ShigActive™, a lytic bacteriophage preparation targeting Shigella spp., in a randomized, placebo-controlled, double-blind Phase 1 clinical trial. Ten participants randomized 4:1 received ShigActive™ or placebo co-administered with sodium bicarbonate orally three times daily for 7 days. Solicited and unsolicited adverse events (AEs) were observed for 29 days. Fifty percent of the subjects receiving ShigActive™ reported mild GI-related symptoms, while one participant experienced moderate fatigue. No serious or medically attended AEs occurred through day 90. Additionally, no significant differences in GI-associated inflammatory mediators or fecal microbiome changes were observed between placebo- and ShigActive™-treated subjects, or from a participants’ baseline value. The results of this first-in-human (FIH) randomized, controlled Phase 1 trial of ShigActive™ demonstrate that it is safe and well tolerated when orally administered with no significant differences compared to placebo controls. Full article
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22 pages, 5713 KiB  
Article
Synergistic Antimicrobial Effects of Phage vB_AbaSi_W9 and Antibiotics against Acinetobacter baumannii Infection
by Yoon-Jung Choi, Shukho Kim, Minsang Shin and Jungmin Kim
Antibiotics 2024, 13(7), 680; https://doi.org/10.3390/antibiotics13070680 - 22 Jul 2024
Viewed by 904
Abstract
Acinetobacter baumannii is a challenging multidrug-resistant pathogen in healthcare. Phage vB_AbaSi_W9 (GenBank: PP146379.1), identified in our previous study, shows lytic activity against 26 (89.66%) of 29 carbapenem-resistant Acinetobacter baumannii (CRAB) strains with various sequence types (STs). It is a promising candidate for CRAB [...] Read more.
Acinetobacter baumannii is a challenging multidrug-resistant pathogen in healthcare. Phage vB_AbaSi_W9 (GenBank: PP146379.1), identified in our previous study, shows lytic activity against 26 (89.66%) of 29 carbapenem-resistant Acinetobacter baumannii (CRAB) strains with various sequence types (STs). It is a promising candidate for CRAB treatment; however, its lytic efficiency is insufficient for complete bacterial lysis. Therefore, this study aimed to investigate the clinical utility of the phage vB_AbaSi_W9 by identifying antimicrobial agents that show synergistic effects when combined with it. The A. baumannii ATCC17978 strain was used as the host for the phage vB_AbaSi_W9. Adsorption and one-step growth assays of the phage vB_AbaSi_W9 were performed at MOIs of 0.001 and 0.01, respectively. Four clinical strains of CRAB belonging to different sequence types, KBN10P04948 (ST191), LIS2013230 (ST208), KBN10P05982 (ST369), and KBN10P05231 (ST451), were used to investigate phage–antibiotic synergy. Five antibiotics were tested at the following concentration: meropenem (0.25–512 µg/mL); colistin, tigecycline, and rifampicin (0.25–256 µg/mL); and ampicillin/sulbactam (0.25/0.125–512/256 µg/mL). The in vitro synergistic effect of the phage and rifampicin was verified through an in vivo mouse infection model. Phage vB_AbaSi_W9 demonstrated 90% adsorption to host cells in 1 min, a 20 min latent period, and a burst size of 114 PFU/cell. Experiments combining phage vB_AbaSi_W9 with antibiotics demonstrated a pronounced synergistic effect against clinical strains when used with tigecycline and rifampicin. In a mouse model infected with CRAB KBN10P04948 (ST191), the group treated with rifampicin (100 μg/mL) and phage vB_AbaSi_W9 (MOI 1) achieved a 100% survival rate—a significant improvement over the phage-only treatment (8.3% survival rate) or antibiotic-only treatment (25% survival rate) groups. The bacteriophage vB_AbaSi_W9 demonstrated excellent synergy against CRAB strains when combined with tigecycline and rifampicin, suggesting potential candidates for phage–antibiotic combination therapy in treating CRAB infections. Full article
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18 pages, 14184 KiB  
Article
Isolation and Characterization of Novel Bacteriophages to Target Carbapenem-Resistant Acinetobacter baumannii
by Yoon-Jung Choi, Shukho Kim, Minsang Shin and Jungmin Kim
Antibiotics 2024, 13(7), 610; https://doi.org/10.3390/antibiotics13070610 - 29 Jun 2024
Cited by 1 | Viewed by 1566
Abstract
The spread of multidrug-resistant Acinetobacter baumannii in hospitals and nursing homes poses serious healthcare challenges. Therefore, we aimed to isolate and characterize lytic bacteriophages targeting carbapenem-resistant Acinetobacter baumannii (CRAB). Of the 21 isolated A. baumannii phages, 11 exhibited potent lytic activities against clinical [...] Read more.
The spread of multidrug-resistant Acinetobacter baumannii in hospitals and nursing homes poses serious healthcare challenges. Therefore, we aimed to isolate and characterize lytic bacteriophages targeting carbapenem-resistant Acinetobacter baumannii (CRAB). Of the 21 isolated A. baumannii phages, 11 exhibited potent lytic activities against clinical isolates of CRAB. Based on host spectrum and RAPD-PCR results, 11 phages were categorized into four groups. Three phages (vB_AbaP_W8, vB_AbaSi_W9, and vB_AbaSt_W16) were further characterized owing to their antibacterial efficacy, morphology, and whole-genome sequence and were found to lyse 37.93%, 89.66%, and 37.93%, respectively, of the 29 tested CRAB isolates. The lytic spectrum of phages varied depending on the multilocus sequence type (MLST) of the CRAB isolates. The three phages contained linear double-stranded DNA genomes, with sizes of 41,326–166,741 bp and GC contents of 34.4–35.6%. Genome-wide phylogenetic analysis and single gene-based tree construction revealed no correlation among the three phages. Moreover, no genes were associated with lysogeny, antibiotic resistance, or bacterial toxins. Therefore, the three novel phages represent potential candidates for phage therapy against CRAB infections. Full article
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16 pages, 2550 KiB  
Article
Isolation, Characterization, and Complete Genome Sequence of Escherichia Phage KIT06 Which Infects Nalidixic Acid-Resistant Escherichia coli
by Nguyen Song Han, Mana Harada, Nguyen Huan Pham-Khanh and Kaeko Kamei
Antibiotics 2024, 13(7), 581; https://doi.org/10.3390/antibiotics13070581 - 23 Jun 2024
Viewed by 1345
Abstract
Escherichia coli (E. coli) is one of the most common sources of infection in humans and animals. The emergence of E. coli which acquires resistance to various antibiotics has made treatment difficult. Bacteriophages can be considered promising agents to expand the [...] Read more.
Escherichia coli (E. coli) is one of the most common sources of infection in humans and animals. The emergence of E. coli which acquires resistance to various antibiotics has made treatment difficult. Bacteriophages can be considered promising agents to expand the options for the treatment of antibiotic-resistant bacteria. This study describes the isolation and characterization of Escherichia phage KIT06, which can infect E. coli resistant to the quinolone antibiotic nalidixic acid. Phage virions possess an icosahedral head that is 93 ± 8 nm in diameter and a contractile tail (116 ± 12 nm × 13 ± 5 nm). The phage was found to be stable under various thermal and pH conditions. A one-step growth curve showed that the latent time of the phage was 20 min, with a burst size of 28 particles per infected cell. Phage KIT06 infected 7 of 12 E. coli strains. It inhibited the growth of the host bacterium and nalidixic acid-resistant E. coli. The lipopolysaccharide and outer membrane proteins of E. coli, tsx and btuB, are phage receptors. Phage KIT06 is a new species of the genus Tequatrovirus with a genome of 167,059 bp consisting of 264 open reading frames (ORFs) that encode gene products related to morphogenesis, replication, regulation, and host lysis. The lack of genes encoding integrase or excisionase indicated that this phage was lytic. Thus, KIT06 could potentially be used to treat antibiotic-resistant E. coli using phage therapy. However, further studies are essential to understand its use in combination with other antimicrobial agents and its safe use in such applications. Full article
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28 pages, 8278 KiB  
Article
Use of the Naturally Occurring Bacteriophage Grouping Model for the Design of Potent Therapeutic Cocktails
by Tea Glonti, Michael Goossens, Christel Cochez, Sabrina Green, Sayali Gorivale, Jeroen Wagemans, Rob Lavigne and Jean-Paul Pirnay
Antibiotics 2024, 13(5), 385; https://doi.org/10.3390/antibiotics13050385 - 24 Apr 2024
Viewed by 2702
Abstract
The specificity of phages and their ability to evolve and overcome bacterial resistance make them potentially useful as adjuncts in the treatment of antibiotic-resistant bacterial infections. The goal of this study was to mimic a natural grouping of phages of interest and to [...] Read more.
The specificity of phages and their ability to evolve and overcome bacterial resistance make them potentially useful as adjuncts in the treatment of antibiotic-resistant bacterial infections. The goal of this study was to mimic a natural grouping of phages of interest and to evaluate the nature of their proliferation dynamics with bacteria. We have, for the first time, transferred naturally occurring phage groups directly from their sources of isolation to in vitro and identified 13 P. aeruginosa and 11 K. pneumoniae phages of 18 different genera, whose host range was grouped as 1.2–17%, 28–48% and 60–87%, using a large collection of P. aeruginosa (n = 102) and K. pneumoniae (n = 155) strains carrying different virulence factors and phage binding receptors. We introduced the interpretation model curve for phage liquid culturing, which allows easy and quick analysis of bacterial and phage co-proliferation and growth of phage-resistant mutants (PRM) based on qualitative and partially quantitative evaluations. We assayed phage lytic activities both individually and in 14 different cocktails on planktonic bacterial cultures, including three resistotypes of P. aeruginosa (PAO1, PA14 and PA7) and seven K. pneumoniae strains of different capsular serotypes. Based on the results, the natural phage cocktails designed and tested in this study largely performed well and inhibited PRM growth either synergistically or in proto-cooperation. This study contributes to the knowledge of phage behavior in cocktails and the formulation of therapeutic phage preparations. The paper also provides a detailed description of the methods of working with phages. Full article
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24 pages, 2728 KiB  
Article
RETRACTED: Isolation and Characterization of a Novel Lytic Phage, vB_PseuP-SA22, and Its Efficacy against Carbapenem-Resistant Pseudomonas aeruginosa
by Addisu D. Teklemariam, Rashad R. Al-Hindi, Mona G. Alharbi, Ibrahim Alotibi, Sheren A. Azhari, Ishtiaq Qadri, Turki Alamri, Ahmed Esmael and Steve Harakeh
Antibiotics 2023, 12(3), 497; https://doi.org/10.3390/antibiotics12030497 - 2 Mar 2023
Cited by 8 | Viewed by 3422 | Retraction
Abstract
Carbapenem-resistant Pseudomonas aeruginosa (CRPA) poses a serious public health threat in multiple clinical settings. In this study, we detail the isolation of a lytic bacteriophage, vB_PseuP-SA22, from wastewater using a clinical strain of CRPA. Transmission electron microscopy (TEM) analysis identified that the phage [...] Read more.
Carbapenem-resistant Pseudomonas aeruginosa (CRPA) poses a serious public health threat in multiple clinical settings. In this study, we detail the isolation of a lytic bacteriophage, vB_PseuP-SA22, from wastewater using a clinical strain of CRPA. Transmission electron microscopy (TEM) analysis identified that the phage had a podovirus morphology, which agreed with the results of whole genome sequencing. BLASTn search allowed us to classify vB_PseuP-SA22 into the genus Bruynoghevirus. The genome of vB_PseuP-SA22 consisted of 45,458 bp of double-stranded DNA, with a GC content of 52.5%. Of all the open reading frames (ORFs), only 26 (44.8%) were predicted to encode certain functional proteins, whereas the remaining 32 (55.2%) ORFs were annotated as sequences coding functionally uncharacterized hypothetical proteins. The genome lacked genes coding for toxins or markers of lysogenic phages, including integrases, repressors, recombinases, or excisionases. The phage produced round, halo plaques with a diameter of 1.5 ± 2.5 mm on the bacterial lawn. The TEM revealed that vB_PseuP-SA22 has an icosahedral head of 57.5 ± 4.5 nm in length and a short, non-contractile tail (19.5 ± 1.4 nm). The phage showed a latent period of 30 min, a burst size of 300 PFU/infected cells, and a broad host range. vB_PseuP-SA22 was found to be stable between 4–60 °C for 1 h, while the viability of the virus was reduced at temperatures above 60 °C. The phage showed stability at pH levels between 5 and 11. vB_PauP-SA22 reduced the number of live bacteria in P. aeruginosa biofilm by almost five logs. The overall results indicated that the isolated phage could be a candidate to control CRPA infections. However, experimental in vivo studies are essential to ensure the safety and efficacy of vB_PauP-SA22 before its use in humans. Full article
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18 pages, 2312 KiB  
Article
Design of a Bacteriophage Cocktail Active against Shigella Species and Testing of Its Therapeutic Potential in Galleria mellonella
by Andrey A. Filippov, Wanwen Su, Kirill V. Sergueev, Richard T. Kevorkian, Erik C. Snesrud, Apichai Srijan, Yunxiu He, Derrick E. Fouts, Woradee Lurchachaiwong, Patrick T. McGann, Damon W. Ellison, Brett E. Swierczewski and Mikeljon P. Nikolich
Antibiotics 2022, 11(11), 1659; https://doi.org/10.3390/antibiotics11111659 - 19 Nov 2022
Cited by 1 | Viewed by 2438
Abstract
Shigellosis is a leading global cause of diarrheal disease and travelers’ diarrhea now being complicated by the dissemination of antibiotic resistance, necessitating the development of alternative antibacterials such as therapeutic bacteriophages (phages). Phages with lytic activity against Shigella strains were isolated from sewage. [...] Read more.
Shigellosis is a leading global cause of diarrheal disease and travelers’ diarrhea now being complicated by the dissemination of antibiotic resistance, necessitating the development of alternative antibacterials such as therapeutic bacteriophages (phages). Phages with lytic activity against Shigella strains were isolated from sewage. The genomes of 32 phages were sequenced, and based on genomic comparisons belong to seven taxonomic genera: Teetrevirus, Teseptimavirus, Kayfunavirus, Tequatrovirus, Mooglevirus, Mosigvirus and Hanrivervirus. Phage host ranges were determined with a diverse panel of 95 clinical isolates of Shigella from Southeast Asia and other geographic regions, representing different species and serotypes. Three-phage mixtures were designed, with one possessing lytic activity against 89% of the strain panel. This cocktail exhibited lytic activity against 100% of S. sonnei isolates, 97.2% of S. flexneri (multiple serotypes) and 100% of S. dysenteriae serotypes 1 and 2. Another 3-phage cocktail composed of two myophages and one podophage showed both a broad host range and the ability to completely sterilize liquid culture of a model virulent strain S. flexneri 2457T. In a Galleria mellonella model of lethal infection with S. flexneri 2457T, this 3-phage cocktail provided a significant increase in survival. Full article
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9 pages, 1131 KiB  
Communication
Combination Treatment for Inhibition of the Growth of Staphylococcus aureus with Recombinant SAP8 Endolysin and Nisin
by Seon-Gyu Kim, Shehzad Abid Khan, Young-Duck Lee, Jong-Hyun Park and Gi-Seong Moon
Antibiotics 2022, 11(9), 1185; https://doi.org/10.3390/antibiotics11091185 - 2 Sep 2022
Cited by 3 | Viewed by 1941
Abstract
Staphylococcus aureus, a pathogenic species of genus Staphylococcus involved in foodborne illness always remain among the top priorities of the world major concerns. In the present study, we have used recombinant SAP8 endolysin from the bacteriophage SAP8 and commercial nisin to inhibit [...] Read more.
Staphylococcus aureus, a pathogenic species of genus Staphylococcus involved in foodborne illness always remain among the top priorities of the world major concerns. In the present study, we have used recombinant SAP8 endolysin from the bacteriophage SAP8 and commercial nisin to inhibit the viability of pathogenic S. aureus KCTC 3881 cells; however, the approach was not identified as cost-effective. A gradual decrease in the viable S. aureus KCTC 3881 cell counts was observed with an increase in the concentrations of recombinant SAP8 endolysin and nisin. However, combined treatment with recombinant SAP8 endolysin and nisin decreased the viable S. aureus KCTC 3881 cell counts in a significant manner. The combination of 0.01 µM of recombinant SAP8 endolysin with 9 IU/mL and 18 IU/mL of nisin demonstrated a promising decrease in the viable cell counts of the strain. Under the scanning electron microscope, the combination treatment with 0.01 µM of recombinant SAP8 endolysin and 18 IU/mL of nisin showed complete cellular destruction of S. aureus KCTC 3881. We propose that a combination of recombinant SAP8 endolysin and nisin could be a strong alternative to antibiotics to control the growth of S. aureus including MRSA. Full article
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