scholarly journals Phage therapy: awakening a sleeping giant

2017 ◽  
Vol 1 (1) ◽  
pp. 93-103 ◽  
Author(s):  
Dwayne R. Roach ◽  
Laurent Debarbieux
Keyword(s):  
Bacterial Resistance ◽  
Phage Therapy ◽  
Therapeutic Modality ◽  
Resistant Bacteria ◽  
Mammalian Host ◽  
Host Immune Responses ◽  
Therapy Effectiveness ◽  
New Antibiotics ◽  
Key Aspects ◽  
Therapy Strategies

For a century, bacterial viruses called bacteriophages have been exploited as natural antibacterial agents. However, their medicinal potential has not yet been exploited due to readily available and effective antibiotics. After years of extensive use, both properly and improperly, antibiotic-resistant bacteria are becoming more prominent and represent a worldwide public health threat. Most importantly, new antibiotics are not progressing at the same rate as the emergence of resistance. The therapeutic modality of bacteriophages, called phage therapy, offers a clinical option to combat bacteria associated with diseases. Here, we discuss traditional phage therapy approaches, as well as how synthetic biology has allowed for the creation of designer phages for new clinical applications. To implement these technologies, several key aspects and challenges still need to be addressed, such as narrow spectrum, safety, and bacterial resistance. We will summarize our current understanding of how phage treatment elicits mammalian host immune responses, as well bacterial phage resistance development, and the potential impact each will have on phage therapy effectiveness. We conclude by discussing the need for a paradigm shift on how phage therapy strategies are developed.

scholarly journals How to Train Your Phage: The Recent Efforts in Phage Training

Biologics ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 70-88
Author(s):  
Abdallah Abdelsattar ◽  
Alyaa Dawooud ◽  
Nouran Rezk ◽  
Salsabil Makky ◽  
Anan Safwat ◽  
...  
Keyword(s):  
Host Range ◽  
Pathogenic Bacteria ◽  
Bacterial Resistance ◽  
Phage Therapy ◽  
Current Knowledge ◽  
Lytic Replication ◽  
Resistant Bacteria ◽  
Infection Cycles ◽  
Different Strains ◽  
Specific Species

Control of pathogenic bacteria by deliberate application of predatory phages has potential as a powerful therapy against antibiotic-resistant bacteria. The key advantages of phage biocontrol over antibacterial chemotherapy are: (1) an ability to self-propagate inside host bacteria, (2) targeted predation of specific species or strains of bacteria, (3) adaptive molecular machinery to overcome resistance in target bacteria. However, realizing the potential of phage biocontrol is dependent on harnessing or adapting these responses, as many phage species switch between lytic infection cycles (resulting in lysis) and lysogenic infection cycles (resulting in genomic integration) that increase the likelihood of survival of the phage in response to external stress or host depletion. Similarly, host range will need to be optimized to make phage therapy medically viable whilst avoiding the potential for deleteriously disturbing the commensal microbiota. Phage training is a new approach to produce efficient phages by capitalizing on the evolved response of wild-type phages to bacterial resistance. Here we will review recent studies reporting successful trials of training different strains of phages to switch into lytic replication mode, overcome bacterial resistance, and increase their host range. This review will also highlight the current knowledge of phage training and future implications in phage applications and phage therapy and summarize the recent pipeline of the magistral preparation to produce a customized phage for clinical trials and medical applications.

scholarly journals Broadscale phage therapy is unlikely to select for widespread evolution of bacterial resistance to virus infection

2020 ◽  
Vol 6 (2) ◽  
Author(s):  
Frederick M Cohan ◽  
Matthew Zandi ◽  
Paul E Turner
Keyword(s):  
Bacterial Resistance ◽  
Phage Therapy ◽  
Patient Treatment ◽  
Resistant Bacteria ◽  
Bacterial Populations ◽  
Recent Success ◽  
Adaptive Value ◽  
Global Spread ◽  
Classic Approach ◽  
Selection For

Abstract Multi-drug resistant bacterial pathogens are alarmingly on the rise, signaling that the golden age of antibiotics may be over. Phage therapy is a classic approach that often employs strictly lytic bacteriophages (bacteria-specific viruses that kill cells) to combat infections. Recent success in using phages in patient treatment stimulates greater interest in phage therapy among Western physicians. But there is concern that widespread use of phage therapy would eventually lead to global spread of phage-resistant bacteria and widespread failure of the approach. Here, we argue that various mechanisms of horizontal genetic transfer (HGT) have largely contributed to broad acquisition of antibiotic resistance in bacterial populations and species, whereas similar evolution of broad resistance to therapeutic phages is unlikely. The tendency for phages to infect only particular bacterial genotypes limits their broad use in therapy, in turn reducing the likelihood that bacteria could acquire beneficial resistance genes from distant relatives via HGT. We additionally consider whether HGT of clustered regularly interspaced short palindromic repeats (CRISPR) immunity would thwart generalized use of phages in therapy, and argue that phage-specific CRISPR spacer regions from one taxon are unlikely to provide adaptive value if horizontally-transferred to other taxa. For these reasons, we conclude that broadscale phage therapy efforts are unlikely to produce widespread selection for evolution of bacterial resistance.

scholarly journals Phage Therapy -- Everything Old Is New again

2006 ◽  
Vol 17 (5) ◽  
pp. 297-306 ◽  
Author(s):  
Andrew M Kropinski
Keyword(s):  
Bacterial Infections ◽  
Phage Therapy ◽  
Therapeutic Modality ◽  
Resistant Bacteria ◽  
Pathogenic Potential ◽  
Microbial Genetics ◽  
Antibiotic Resistant ◽  
Vector Systems ◽  
Variable Success ◽  
Bacterial Viruses

The study of bacterial viruses (bacteriophages or phages) proved pivotal in the nascence of the disciplines of molecular biology and microbial genetics, providing important information on the central processes of the bacterial cell (DNA replication, transcription and translation) and on how DNA can be transferred from one cell to another. As a result of the pioneering genetics studies and modern genomics, it is now known that phages have contributed to the evolution of the microbial cell and to its pathogenic potential. Because of their ability to transmit genes, phages have been exploited to develop cloning vector systems. They also provide a plethora of enzymes for the modern molecular biologist. Until the introduction of antibiotics, phages were used to treat bacterial infections (with variable success). Western science is now having to re-evaluate the application of phage therapy -- a therapeutic modality that never went out of vogue in Eastern Europe -- because of the emergence of an alarming number of antibiotic-resistant bacteria. The present article introduces the reader to phage biology, and the benefits and pitfalls of phage therapy in humans and animals.

scholarly journals Novel Group of Leaderless Multipeptide Bacteriocins from Gram-Positive Bacteria

2016 ◽  
Vol 82 (17) ◽  
pp. 5216-5224 ◽  
Author(s):  
Kirill V. Ovchinnikov ◽  
Hai Chi ◽  
Ibrahim Mehmeti ◽  
Helge Holo ◽  
Ingolf F. Nes ◽  
...  
Keyword(s):  
Amino Acids ◽  
Antimicrobial Activity ◽  
Bacterial Resistance ◽  
Raw Milk ◽  
Peptide Sequencing ◽  
Homology Search ◽  
Resistant Bacteria ◽  
Content Type ◽  
New Antibiotics ◽  
Inhibitory Spectrum

ABSTRACTFrom raw milk we found 10Lactococcus garvieaeisolates that produce a new broad-spectrum bacteriocin. Though the isolates were obtained from different farms, they turned out to possess identical inhibitory spectra, fermentation profiles of sugars, and repetitive sequence-based PCR (rep-PCR) DNA patterns, indicating that they produce the same bacteriocin. One of the isolates (L. garvieaeKS1546) was chosen for further assessment. Purification and peptide sequencing combined with genome sequencing revealed that the antimicrobial activity was due to a bacteriocin unit composed of three similar peptides of 32 to 34 amino acids. The three peptides are produced without leader sequences, and their genes are located next to each other in an operon-like structure, adjacent to the genes normally involved in bacteriocin transport (ABC transporter) and self-immunity. The bacteriocin, termed garvicin KS (GarKS), showed sequence homology to four multipeptide bacteriocins in databases: the known staphylococcal aureocin A70, consisting of four peptides, and three unannotated putative multipeptide bacteriocins produced byBacillus cereus. All these multipeptide bacteriocin loci show conserved genetic organization, including being located adjacent to conserved genetic determinants (Cro/cI and integrase) which are normally associated with mobile genetic elements or genome rearrangements. The antimicrobial activity of all multipeptide bacteriocins was confirmed with synthetic peptides, and all were shown to have broad antimicrobial spectra, with GarKS being the most active of them. The inhibitory spectrum of GarKS includes important pathogens belonging to the generaStaphylococcus,Bacillus,Listeria, andEnterococcus.IMPORTANCEBacterial resistance to antibiotics is a very serious global problem. There are no new antibiotics with novel antimicrobial mechanisms in clinical trials. Bacteriocins use antimicrobial mechanisms different from those of antibiotics and can kill antibiotic-resistant bacteria, but the number of bacteriocins with very broad antimicrobial spectra is very small. In this study, we have found and purified a novel three-peptide bacteriocin, garvicin KS. By homology search, we were able to find one known and three novel sequence-related bacteriocins consisting of 3 or 4 peptides. None of the peptides has modified amino acids in its sequence. Thus, the activity of all bacteriocins was confirmed with chemically synthesized peptides. All of them, especially garvicin KS, have very broad antibacterial spectra, thus representing a great potential in antimicrobial applications in the food industry and medicine.

scholarly journals Evolution of Bacterial Cross-Resistance to Lytic Phages and Albicidin Antibiotic

2021 ◽  
Vol 12 ◽  
Author(s):  
Kaitlyn E. Kortright ◽  
Simon Doss-Gollin ◽  
Benjamin K. Chan ◽  
Paul E. Turner
Keyword(s):  
Bacterial Resistance ◽  
Phage Therapy ◽  
Cross Resistance ◽  
Resistant Bacteria ◽  
Wild Type ◽  
E Coli ◽  
High Resource ◽  
Bacterial Mutants ◽  
Global Increase ◽  
Evolutionary Consequences

Due to concerns over the global increase of antibiotic-resistant bacteria, alternative antibacterial strategies, such as phage therapy, are increasingly being considered. However, evolution of bacterial resistance to new therapeutics is almost a certainty; indeed, it is possible that resistance to alternative treatments might result in an evolved trade-up such as enhanced antibiotic resistance. Here, we hypothesize that selection for Escherichia coli bacteria to resist phage T6, phage U115, or albicidin, a DNA gyrase inhibitor, should often result in a pleiotropic trade-up in the form of cross-resistance, because all three antibacterial agents interact with the Tsx porin. Selection imposed by any one of the antibacterials resulted in cross-resistance to all three of them, in each of the 29 spontaneous bacterial mutants examined in this study. Furthermore, cross-resistance did not cause measurable fitness (growth) deficiencies for any of the bacterial mutants, when competed against wild-type E. coli in both low-resource and high-resource environments. A combination of whole-genome and targeted sequencing confirmed that mutants differed from wild-type E. coli via change(s) in the tsx gene. Our results indicate that evolution of cross-resistance occurs frequently in E. coli subjected to independent selection by phage T6, phage U115 or albicidin. This study cautions that deployment of new antibacterial therapies such as phage therapy, should be preceded by a thorough investigation of evolutionary consequences of the treatment, to avoid the potential for evolved trade-ups.

scholarly journals Phage Therapy: Consider the Past, Embrace the Future

2020 ◽  
Vol 10 (21) ◽  
pp. 7654
Author(s):  
Junwei Wei ◽  
Nan Peng ◽  
Yunxiang Liang ◽  
Keke Li ◽  
Yingjun Li
Keyword(s):  
Phage Therapy ◽  
Alternative Therapies ◽  
Resistant Bacteria ◽  
Application Process ◽  
Antibiotic Resistant ◽  
The Past ◽  
The Future ◽  
New Antibiotics ◽  
Potential Risks ◽  
Delivery Technology

Antibiotic-resistant bacteria infections pose a threat to public health. Considering the difficulty in developing new antibiotics, it is an urgent need to develop alternative therapies against bacterial pathogens. Bacteriophages (phages) are evaluated as potential substitutes or adjuncts of antibiotics because they are abundant in nature and could specifically lyse bacteria. In this review, we briefly introduce phage therapy and its advantages compared with traditional antibiotic therapy. We also summarize new emerging phage technologies, such as CRISPR-Cas, synthetic phages, etc., and discuss some possible obstacles and potential risks in the application process. We believe that, with the advancement in synthetic biology and delivery technology, phage therapy has broad prospects in the future.

scholarly journals Pharmacologically Aware Phage Therapy: Pharmacodynamic and Pharmacokinetic Obstacles to Phage Antibacterial Action in Animal and Human Bodies

2019 ◽  
Vol 83 (4) ◽  
Author(s):  
Krystyna Dąbrowska ◽  
Stephen T. Abedon
Keyword(s):  
Bacterial Infections ◽  
Bacterial Resistance ◽  
Phage Therapy ◽  
Anecdotal Evidence ◽  
International Crisis ◽  
Widespread Implementation ◽  
Therapy Effectiveness ◽  
Low Toxicity ◽  
Body Compartments ◽  
Further Development

SUMMARY The use of viruses infecting bacteria (bacteriophages or phages) to treat bacterial infections has been ongoing clinically for approximately 100 years. Despite that long history, the growing international crisis of resistance to standard antibiotics, abundant anecdotal evidence of efficacy, and one successful modern clinical trial of efficacy, this phage therapy is not yet a mainstream approach in medicine. One explanation for why phage therapy has not been subject to more widespread implementation is that phage therapy research, both preclinical and clinical, can be insufficiently pharmacologically aware. Consequently, here we consider the pharmacological obstacles to phage therapy effectiveness, with phages in phage therapy explicitly being considered to serve as drug equivalents. The study of pharmacology has traditionally been differentiated into pharmacokinetic and pharmacodynamic aspects. We therefore separately consider the difficulties that phages as virions can have in traveling through body compartments toward reaching their target bacteria (pharmacokinetics) and the difficulties that phages can have in exerting antibacterial activity once they have reached those bacteria (pharmacodynamics). The latter difficulties, at least in part, are functions of phage host range and bacterial resistance to phages. Given the apparently low toxicity of phages and the minimal side effects of phage therapy as practiced, phage therapy should be successful so long as phages can reach the targeted bacteria in sufficiently high numbers, adsorb, and then kill those bacteria. Greater awareness of what obstacles to this success generally or specifically can exist, as documented in this review, should aid in the further development of phage therapy toward wider use.

scholarly journals Phage Resistance Mechanisms Increase Colistin Sensitivity in Acinetobacter baumannii

2021 ◽  
Author(s):  
Xiaoqing Wang ◽  
Belinda Loh ◽  
Yunsong Yu ◽  
Xiaoting Hua ◽  
Sebastian Leptihn
Keyword(s):  
Bacterial Infections ◽  
Bacterial Resistance ◽  
Phage Therapy ◽  
Resistance Mechanism ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Resistant Bacteria ◽  
Phage Resistance ◽  
Colistin Resistance ◽  
Increased Sensitivity

Few emergency-use antibiotics remain for the treatment of multidrug-resistant bacterial infections. Infections with resistant bacteria are becoming increasingly common. Phage therapy has reemerged as a promising strategy to treat such infections, as microbial viruses are not affected by bacterial resistance to antimicrobial compounds. However, phage therapy is impeded by rapid emergence of phage-resistant bacteria during therapy. In this work, we studied phage-resistance of colistin sensitive and resistant A. baumannii strains. Using whole genome sequencing, we determined that phage resistant strains displayed mutations in genes that alter the architecture of the bacterial envelope. In contrast to previous studies where phage-escape mutants showed decreased binding of phages to the bacterial envelope, we obtained several not uninfectable isolates that allowed similar phage adsorption compared to the susceptible strain. When phage-resistant bacteria emerged in the absence of antibiotics, we observed that the colistin resistance levels often decreased, while the antibiotic resistance mechanism per se remained unaltered. In particular the two mutated genes that conveyed phage resistance, a putative amylovoran- biosynthesis and a lipo-oligosaccharide (LOS) biosynthesis gene, impact colistin resistance as the mutations increased sensitivity to the antibiotic.

scholarly journals Phage-Derived Antibacterials: Harnessing the Simplicity, Plasticity, and Diversity of Phages

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 268 ◽  
Author(s):  
Bi-o Kim ◽  
Eun Kim ◽  
Yeon-Ji Yoo ◽  
Hee-Won Bae ◽  
In-Young Chung ◽  
...  
Keyword(s):  
Immune Responses ◽  
Phage Therapy ◽  
Phage Genome ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Proof Of Concept ◽  
Bacterial Populations ◽  
Host Immune Responses ◽  
Product Engineering ◽  
Opening Up

Despite the successful use of antibacterials, the emergence of multidrug-resistant bacteria has become a serious threat to global healthcare. In this era of antibacterial crisis, bacteriophages (phages) are being explored as an antibacterial treatment option since they possess a number of advantages over conventional antibacterials, especially in terms of specificity and biosafety; phages specifically lyse target bacteria while not affecting normal and/or beneficial bacteria and display little or no toxicity in that they are mainly composed of proteins and nucleic acids, which consequently significantly reduces the time and cost involved in antibacterial development. However, these benefits also create potential issues regarding antibacterial spectra and host immunity; the antibacterial spectra being very narrow when compared to those of chemicals, with the phage materials making it possible to trigger host immune responses, which ultimately disarm antibacterial efficacy upon successive treatments. In addition, phages play a major role in horizontal gene transfer between bacterial populations, which poses serious concerns for the potential of disastrous consequences regarding antibiotic resistance. Fortunately, however, recent advancements in synthetic biology tools and the speedy development of phage genome resources have allowed for research on methods to circumvent the potentially disadvantageous aspects of phages. These novel developments empower research which goes far beyond traditional phage therapy approaches, opening up a new chapter for phage applications with new antibacterial platforms. Herein, we not only highlight the most recent synthetic phage engineering and phage product engineering studies, but also discuss a new proof-of-concept for phage-inspired antibacterial design based on the studies undertaken by our group.

scholarly journals Multidrug and Pan-Antibiotic Resistance—The Role of Antimicrobial and Synergistic Essential Oils: A Review

2020 ◽  
Vol 15 (10) ◽  
pp. 1934578X2096259
Author(s):  
Karen Boren ◽  
AliceAnn Crown ◽  
Richard Carlson
Keyword(s):  
Essential Oils ◽  
Bacterial Resistance ◽  
Fungal Infections ◽  
Multidrug Resistant ◽  
World Health ◽  
Resistant Bacteria ◽  
Bacterial Membranes ◽  
New Antibiotics ◽  
Clinical Benefits

Bacterial resistance to antibiotics continues to be a grave threat to human health. Because antibiotics are no longer a lucrative market for pharmaceutical companies, the development of new antibiotics has slowed to a crawl. The World Health Organization reported that the 8 new bacterial agents approved since July 2017 had limited clinical benefits. While a cohort of biopharmaceutical companies recently announced plans to develop 2-4 new antibiotics by 2030, we needn’t wait a decade to find innovative antibiotic candidates. Essential oils (EOs) have long been known as antibacterial agents with wide-ranging arsenals. Many are able to penetrate the bacterial membrane and may also be effective against bacterial defenses such as biofilms, efflux pumps, and quorum sensing. EOs have been documented to fight drug-resistant bacteria alone and/or combined with antibiotics. This review will summarize research showing the significant role of EOs as nonconventional regimens against the worldwide spread of antibiotic-resistant pathogens. The authors conducted a 4-year search of the US National Library of Medicine (PubMed) for relevant EO studies against methicillin-resistant Staphylococcus aureus, multidrug-resistant (MDR) Escherichia coli, EO combinations/synergy with antibiotics, against MDR fungal infections, showing the ability to permeate bacterial membranes, and against the bacterial defenses listed above. EOs are readily available and are a needed addition to the arsenal against resistant pathogens.

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