Systematic analysis of putative phage-phage interactions on minimum-sized phage cocktails. - Related Documents




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947101.0000Systematic analysis of putative phage-phage interactions on minimum-sized phage cocktails. The application of bacteriophages as antibacterial agents has many benefits in the "post-antibiotic age". To increase the number of successfully targeted bacterial strains, phage cocktails, instead of a single phage, are commonly formulated. Nevertheless, there is currently no consensus pipeline for phage cocktail development. Thus, although large cocktails increase the spectrum of activity, they could produce side effects such as the mobilization of virulence or antibiotic resistance genes. On the other hand, coinfection (simultaneous infection of one host cell by several phages) might reduce the potential for bacteria to evolve phage resistance, but some antagonistic interactions amongst phages might be detrimental for the outcome of phage cocktail application. With this in mind, we introduce here a new method, which considers the host range and each individual phage-host interaction, to design the phage mixtures that best suppress the target bacteria while minimizing the number of phages to restrict manufacturing costs. Additionally, putative phage-phage interactions in cocktails and phage-bacteria networks are compared as the understanding of the complex interactions amongst bacteriophages could be critical in the development of realistic phage therapy models in the future.202235165352
959110.9999Interaction of phages, bacteria, and the human immune system: Evolutionary changes in phage therapy. Phages and bacteria are known to undergo dynamic and co-evolutionary arms race interactions in order to survive. Recent advances from in vitro and in vivo studies have improved our understanding of the complex interactions between phages, bacteria, and the human immune system. This insight is essential for the development of phage therapy to battle the growing problems of antibiotic resistance. It is also pivotal to prevent the development of phage-resistance during the implementation of phage therapy in the clinic. In this review, we discuss recent progress of the interactions between phages, bacteria, and the human immune system and its clinical application for phage therapy. Proper phage therapy design will ideally produce large burst sizes, short latent periods, broad host ranges, and a low tendency to select resistance.201931145517
953320.9999The disparate effects of bacteriophages on antibiotic-resistant bacteria. Faced with the crisis of multidrug-resistant bacteria, bacteriophages, viruses that infect and replicate within bacteria, have been reported to have both beneficial and detrimental effects with respect to disease management. Bacteriophages (phages) have important ecological and evolutionary impacts on their bacterial hosts and have been associated with therapeutic use to kill bacterial pathogens, but can lead to the transmission of antibiotic resistance. Although the process known as transduction has been reported for many bacterial species by classic and modern genetic approaches, its contribution to the spread of antibiotic resistance in nature remains unclear. In addition, detailed molecular studies have identified phages residing in bacterial genomes, revealing unexpected interactions between phages and their bacterial hosts. Importantly, antibiotics can induce the production of phages and phage-encoded products, disseminating these viruses and virulence-related genes, which have dangerous consequences for disease severity. These unwanted side-effects of antibiotics cast doubt on the suitability of some antimicrobial treatments and may require new strategies to prevent and limit the selection for virulence. Foremost among these treatments is phage therapy, which could be used to treat many bacterial infectious diseases and confront the pressing problem of antibiotic resistance in pathogenic bacteria. This review discusses the interactions between bacteriophages, antibiotics, and bacteria and provides an integrated perspective that aims to inspire the development of successful antibacterial therapies.201830302018
947230.9999Bacteriophage and Bacterial Susceptibility, Resistance, and Tolerance to Antibiotics. Bacteriophages, viruses that infect and replicate within bacteria, impact bacterial responses to antibiotics in complex ways. Recent studies using lytic bacteriophages to treat bacterial infections (phage therapy) demonstrate that phages can promote susceptibility to chemical antibiotics and that phage/antibiotic synergy is possible. However, both lytic and lysogenic bacteriophages can contribute to antimicrobial resistance. In particular, some phages mediate the horizontal transfer of antibiotic resistance genes between bacteria via transduction and other mechanisms. In addition, chronic infection filamentous phages can promote antimicrobial tolerance, the ability of bacteria to persist in the face of antibiotics. In particular, filamentous phages serve as structural elements in bacterial biofilms and prevent the penetration of antibiotics. Over time, these contributions to antibiotic tolerance favor the selection of resistance clones. Here, we review recent insights into bacteriophage contributions to antibiotic susceptibility, resistance, and tolerance. We discuss the mechanisms involved in these effects and address their impact on bacterial fitness.202235890320
947340.9999The role of the animal host in the management of bacteriophage resistance during phage therapy. Multi-drug-resistant bacteria are associated with significantly higher morbidity and mortality. The possibilities for discovering new antibiotics are limited, but phage therapy - the use of bacteriophages (viruses infecting bacteria) to cure infections - is now being investigated as an alternative or complementary treatment to antibiotics. However, one of the major limitations of this approach lies in the antagonistic coevolution between bacteria and bacteriophages, which determines the ultimate success or failure of phage therapy. Here, we review the possible influence of the animal host on phage resistance and its consequences for the efficacy of phage therapy. We also discuss the value of in vitro assays for anticipating the dynamics of phage resistance observed in vivo.202336512896
937750.9998Experimental Evolution of the TolC-Receptor Phage U136B Functionally Identifies a Tail Fiber Protein Involved in Adsorption through Strong Parallel Adaptation. Bacteriophages have received recent attention for their therapeutic potential to treat antibiotic-resistant bacterial infections. One particular idea in phage therapy is to use phages that not only directly kill their bacterial hosts but also rely on particular bacterial receptors, such as proteins involved in virulence or antibiotic resistance. In such cases, the evolution of phage resistance would correspond to the loss of those receptors, an approach termed evolutionary steering. We previously found that during experimental evolution, phage U136B can exert selection pressure on Escherichia coli to lose or modify its receptor, the antibiotic efflux protein TolC, often resulting in reduced antibiotic resistance. However, for TolC-reliant phages like U136B to be used therapeutically, we also need to study their own evolutionary potential. Understanding phage evolution is critical for the development of improved phage therapies as well as the tracking of phage populations during infection. Here, we characterized phage U136B evolution in 10 replicate experimental populations. We quantified phage dynamics that resulted in five surviving phage populations at the end of the 10-day experiment. We found that phages from all five surviving populations had evolved higher rates of adsorption on either ancestral or coevolved E. coli hosts. Using whole-genome and whole-population sequencing, we established that these higher rates of adsorption were associated with parallel molecular evolution in phage tail protein genes. These findings will be useful in future studies to predict how key phage genotypes and phenotypes influence phage efficacy and survival despite the evolution of host resistance. IMPORTANCE Antibiotic resistance is a persistent problem in health care and a factor that may help maintain bacterial diversity in natural environments. Bacteriophages ("phages") are viruses that specifically infect bacteria. We previously discovered and characterized a phage called U136B, which infects bacteria through TolC. TolC is an antibiotic resistance protein that helps bacteria pump antibiotics out of the cell. Over short timescales, phage U136B can be used to evolutionarily "steer" bacterial populations to lose or modify the TolC protein, sometimes reducing antibiotic resistance. In this study, we investigate whether U136B itself evolves to better infect bacterial cells. We discovered that the phage can readily evolve specific mutations that increase its infection rate. This work will be useful for understanding how phages can be used to treat bacterial infections.202337191555
947660.9998Phage design and directed evolution to evolve phage for therapy. Phage therapy or Phage treatment is the use of bacteriolysing phage in treating bacterial infections by using the viruses that infects and kills bacteria. This technique has been studied and practiced very long ago, but with the advent of antibiotics, it has been neglected. This foregone technique is now witnessing a revival due to development of bacterial resistance. Nowadays, with the awareness of genetic sequence of organisms, it is required that informed choices of phages have to be made for the most efficacious results. Furthermore, phages with the evolving genes are taken into consideration for the subsequent improvement in treating the patients for bacterial diseases. In addition, direct evolution methods are increasingly developing, since these are capable of creating new biological molecules having changed or unique activities, such as, improved target specificity, evolution of novel proteins with new catalytic properties or creation of nucleic acids that are capable of recognizing required pathogenic bacteria. This system is incorporates continuous evolution such as protein or genes are put under continuous evolution by providing continuous mutagenesis with least human intervention. Although, this system providing continuous directed evolution is very effective, it imposes some challenges due to requirement of heavy investment of time and resources. This chapter focuses on development of phage as a therapeutic agent against various bacteria causing diseases and it improvement using direct evolution of proteins and nucleic acids such that they target specific organisms.202337739551
917570.9998Fitness Trade-Offs Resulting from Bacteriophage Resistance Potentiate Synergistic Antibacterial Strategies. Bacteria that cause life-threatening infections in humans are becoming increasingly difficult to treat. In some instances, this is due to intrinsic and acquired antibiotic resistance, indicating that new therapeutic approaches are needed to combat bacterial pathogens. There is renewed interest in utilizing viruses of bacteria known as bacteriophages (phages) as potential antibacterial therapeutics. However, critics suggest that similar to antibiotics, the development of phage-resistant bacteria will halt clinical phage therapy. Although the emergence of phage-resistant bacteria is likely inevitable, there is a growing body of literature showing that phage selective pressure promotes mutations in bacteria that allow them to subvert phage infection, but with a cost to their fitness. Such fitness trade-offs include reduced virulence, resensitization to antibiotics, and colonization defects. Resistance to phage nucleic acid entry, primarily via cell surface modifications, compromises bacterial fitness during antibiotic and host immune system pressure. In this minireview, we explore the mechanisms behind phage resistance in bacterial pathogens and the physiological consequences of acquiring phage resistance phenotypes. With this knowledge, it may be possible to use phages to alter bacterial populations, making them more tractable to current therapeutic strategies.202032094257
959080.9998Recent advances in phage defense systems and potential overcoming strategies. Bacteriophages are effective in the prevention and control of bacteria, and many phage products have been permitted and applied in the field. Because bacteriophages are expected to replace other antimicrobial agents like antibiotics, the antibacterial effect of bacteriophage has attracted widespread attention. Recently, the diversified defense systems discovered in the target host have become potential threats to the continued effective application of phages. Therefore, a systematic summary and in-depth illustration of the interaction between phages and bacteria is conducive to the development of this biological control approach. In this review, we introduce different defense systems in bacteria against phages and emphasize newly discovered defense mechanisms in recent years. Additionally, we draw attention to the striking resemblance between defense system genes and antibiotic resistance genes, which raises concerns about the potential transfer of phage defense systems within bacterial populations and its future impact on phage efficacy. Thus, attention should be given to the effects of phage defense genes in practical applications. This article is not exhaustive, but strategies to overcome phage defense systems are also discussed to further promote more efficient use of phages.202337037289
947790.9998The microbiome-shaping roles of bacteriocins. The microbiomes on human body surfaces affect health in multiple ways. They include not only commensal or mutualistic bacteria but also potentially pathogenic bacteria, which can enter sterile tissues to cause invasive infection. Many commensal bacteria produce small antibacterial molecules termed bacteriocins that have the capacity to eliminate specific colonizing pathogens; as such, bacteriocins have attracted increased attention as potential microbiome-editing tools. Metagenome-based and activity-based screening approaches have strongly expanded our knowledge of the abundance and diversity of bacteriocin biosynthetic gene clusters and the properties of a continuously growing list of bacteriocin classes. The dynamic acquisition, diversification or loss of bacteriocin genes can shape the fitness of a bacterial strain that is in competition with bacteriocin-susceptible bacteria. However, a bacteriocin can only provide a competitive advantage if its fitness benefit exceeds the metabolic cost of production, if it spares crucial mutualistic partner strains and if major competitors cannot develop resistance. In contrast to most currently available antibiotics, many bacteriocins have only narrow activity ranges and could be attractive agents for precision therapy and prevention of infections. A common scientific strategy involving multiple disciplines is needed to uncover the immense potential of microbiome-shaping bacteriocins.202134075213
9622100.9998Stable Neutralization of a Virulence Factor in Bacteria Using Temperate Phage in the Mammalian Gut. Elimination or alteration of select members of the gut microbiota is key to therapeutic efficacy. However, the complexity of these microbial inhabitants makes it challenging to precisely target bacteria. Here, we deliver exogenous genes to specific bacteria by genomic integration of temperate phage for long-lasting modification. As a real-world therapeutic test, we engineered λ phage to transcriptionally repress Shiga toxin by using genetic hybrids between λ and other lambdoid phages to overcome resistance encoded by the virulence-expressing prophage. We show that a single dose of engineered phage propagates throughout the bacterial community and reduces Shiga toxin production in an enteric mouse model of infection without markedly affecting bacterial concentrations. Our work reveals a new framework for transferring functions to bacteria within their native environment.IMPORTANCE With the increasing frequency of antibiotic resistance, it is critical to explore new therapeutic strategies for treating bacterial infections. Here, we use a temperate phage, i.e., one that integrates itself into the bacterial genome, to neutralize the expression of a virulence factor by modifying bacterial function at the genetic level. We show that Shiga toxin production can be significantly reduced in vitro and in the mammalian gut. Alternative to traditional applications of phage therapy that rely on killing bacteria, our genetics-based antivirulence approach introduces a new framework for treating bacterial infections.202031992629
9534110.9998Defining the Benefits of Antibiotic Resistance in Commensals and the Scope for Resistance Optimization. Antibiotic resistance is a major medical and public health challenge, characterized by global increases in the prevalence of resistant strains. The conventional view is that all antibiotic resistance is problematic, even when not in pathogens. Resistance in commensal bacteria poses risks, as resistant organisms can provide a reservoir of resistance genes that can be horizontally transferred to pathogens or may themselves cause opportunistic infections in the future. While these risks are real, we propose that commensal resistance can also generate benefits during antibiotic treatment of human infection, by promoting continued ecological suppression of pathogens. To define and illustrate this alternative conceptual perspective, we use a two-species mathematical model to identify the necessary and sufficient ecological conditions for beneficial resistance. We show that the benefits are limited to species (or strain) interactions where commensals suppress pathogen growth and are maximized when commensals compete with, rather than prey on or otherwise exploit pathogens. By identifying benefits of commensal resistance, we propose that rather than strictly minimizing all resistance, resistance management may be better viewed as an optimization problem. We discuss implications in two applied contexts: bystander (nontarget) selection within commensal microbiomes and pathogen treatment given polymicrobial infections. IMPORTANCE Antibiotic resistance is commonly viewed as universally costly, regardless of which bacterial cells express resistance. Here, we derive an opposing logic, where resistance in commensal bacteria can lead to reductions in pathogen density and improved outcomes on both the patient and public health scales. We use a mathematical model of commensal-pathogen interactions to define the necessary and sufficient conditions for beneficial resistance, highlighting the importance of reciprocal ecological inhibition to maximize the benefits of resistance. More broadly, we argue that determining the benefits as well as the costs of resistances in human microbiomes can transform resistance management from a minimization to an optimization problem. We discuss applied contexts and close with a review of key resistance optimization dimensions, including the magnitude, spectrum, and mechanism of resistance.202336475750
9205120.9998Resistance induction based on the understanding of molecular interactions between plant viruses and host plants. BACKGROUND: Viral diseases cause significant damage to crop yield and quality. While fungi- and bacteria-induced diseases can be controlled by pesticides, no effective approaches are available to control viruses with chemicals as they use the cellular functions of their host for their infection cycle. The conventional method of viral disease control is to use the inherent resistance of plants through breeding. However, the genetic sources of viral resistance are often limited. Recently, genome editing technology enabled the publication of multiple attempts to artificially induce new resistance types by manipulating host factors necessary for viral infection. MAIN BODY: In this review, we first outline the two major (R gene-mediated and RNA silencing) viral resistance mechanisms in plants. We also explain the phenomenon of mutations of host factors to function as recessive resistance genes, taking the eIF4E genes as examples. We then focus on a new type of virus resistance that has been repeatedly reported recently due to the widespread use of genome editing technology in plants, facilitating the specific knockdown of host factors. Here, we show that (1) an in-frame mutation of host factors necessary to confer viral resistance, sometimes resulting in resistance to different viruses and that (2) certain host factors exhibit antiviral resistance and viral-supporting (proviral) properties. CONCLUSION: A detailed understanding of the host factor functions would enable the development of strategies for the induction of a new type of viral resistance, taking into account the provision of a broad resistance spectrum and the suppression of the appearance of resistance-breaking strains.202134454519
9379130.9998Essential phage component induces resistance of bacterial community. Despite extensive knowledge on phage resistance at bacterium level, the resistance of bacterial communities is still not well-understood. Given its ubiquity, it is essential to understand resistance at the community level. We performed quantitative investigations on the dynamics of phage infection in Klebsiella pneumoniae biofilms. We found that the biofilms quickly developed resistance and resumed growth. Instead of mutations, the resistance was caused by unassembled phage tail fibers released by the phage-lysed bacteria. The tail fibers degraded the bacterial capsule essential for infection and induced spreading of capsule loss in the biofilm, and tuning tail fiber and capsule levels altered the resistance. Latent infections sustained in the biofilm despite resistance, allowing stable phage-bacteria coexistence. Last, we showed that the resistance exposed vulnerabilities in the biofilm. Our findings indicate that phage lysate plays important roles in shaping phage-biofilm interactions and open more dimensions for the rational design of strategies to counter bacteria with phage.202439231230
9611140.9998Parallel evolution of Pseudomonas aeruginosa phage resistance and virulence loss in response to phage treatment in vivo and in vitro. With rising antibiotic resistance, there has been increasing interest in treating pathogenic bacteria with bacteriophages (phage therapy). One limitation of phage therapy is the ease at which bacteria can evolve resistance. Negative effects of resistance may be mitigated when resistance results in reduced bacterial growth and virulence, or when phage coevolves to overcome resistance. Resistance evolution and its consequences are contingent on the bacteria-phage combination and their environmental context, making therapeutic outcomes hard to predict. One solution might be to conduct 'in vitro evolutionary simulations' using bacteria-phage combinations from the therapeutic context. Overall, our aim was to investigate parallels between in vitro experiments and in vivo dynamics in a human participant. Evolutionary dynamics were similar, with high levels of resistance evolving quickly with limited evidence of phage evolution. Resistant bacteria-evolved in vitro and in vivo-had lower virulence. In vivo, this was linked to lower growth rates of resistant isolates, whereas in vitro phage resistant isolates evolved greater biofilm production. Population sequencing suggests resistance resulted from selection on de novo mutations rather than sorting of existing variants. These results highlight the speed at which phage resistance can evolve in vivo, and how in vitro experiments may give useful insights for clinical evolutionary outcomes.202235188102
9470150.9998Practical Method for Isolation of Phage Deletion Mutants. The growing concern about multi-drug resistant pathogenic bacteria has led to a renewed interest in the study of bacteriophages as antimicrobials and as therapeutic agents against infectious diseases (phage therapy). Phages to be used for this purpose have to be subjected to in-depth genomic characterization. It is essential to ascribe specific functions to phage genes, which will give information to unravel phage biology and to ensure the lack of undesirable genes, such as virulence and antibiotic resistance genes. Here, we describe a simple protocol for the selection of phage mutants carrying random deletions along the phage genome. Theoretically, any DNA region might be removed with the only requirement that the phage particle viability remains unaffected. This technique is based on the instability of phage particles in the presence of chelating compounds. A fraction of the phage population naturally lacking DNA segments will survive the treatment. Within the context of phages as antimicrobials, this protocol is useful to select lytic variants from temperate phages. In terms of phage efficiency, virulent phages are preferred over temperate ones to remove undesirable bacteria. This protocol has been used to obtain gene mutations that are involved in the lysogenic cycle of phages infecting Gram-positive bacteria (Staphylococcus and Lactobacillus).201831164553
9492160.9998The Search for 'Evolution-Proof' Antibiotics. The effectiveness of antibiotics has been widely compromised by the evolution of resistance among pathogenic bacteria. It would be restored by the development of antibiotics to which bacteria cannot evolve resistance. We first discuss two kinds of 'evolution-proof' antibiotic. The first comprises literally evolution-proof antibiotics to which bacteria cannot become resistant by mutation or horizontal gene transfer. The second category comprises agents to which resistance may arise, but so rarely that it does not become epidemic. The likelihood that resistance to a novel agent will spread is evaluated here by a simple model that includes biological and therapeutic parameters governing the evolution of resistance within hosts and the transmission of resistant strains between hosts. This model leads to the conclusion that epidemic spread is unlikely if the frequency of mutations that confer resistance falls below a defined minimum value, and it identifies potential targets for intervention to prevent the evolution of resistance. Whether or not evolution-proof antibiotics are ever found, searching for them is likely to improve the deployment of new and existing agents by advancing our understanding of how resistance evolves.201829191398
4276170.9998Phages limit the evolution of bacterial antibiotic resistance in experimental microcosms. The evolution of multi-antibiotic resistance in bacterial pathogens, often resulting from de novo mutations, is creating a public health crisis. Phages show promise for combating antibiotic-resistant bacteria, the efficacy of which, however, may also be limited by resistance evolution. Here, we suggest that phages may be used as supplements to antibiotics in treating initially sensitive bacteria to prevent resistance evolution, as phages are unaffected by most antibiotics and there should be little cross-resistance to antibiotics and phages. In vitro experiments using the bacterium Pseudomonas fluorescens, a lytic phage, and the antibiotic kanamycin supported this prediction: an antibiotic-phage combination dramatically decreased the chance of bacterial population survival that indicates resistance evolution, compared with antibiotic treatment alone, whereas the phage alone did not affect bacterial survival. This effect of the combined treatment in preventing resistance evolution was robust to immigration of bacteria from an untreated environment, but not to immigration from environment where the bacteria had coevolved with the phage. By contrast, an isogenic hypermutable strain constructed from the wild-type P. fluorescens evolved resistance to all treatments regardless of immigration, but typically suffered very large fitness costs. These results suggest that an antibiotic-phage combination may show promise as an antimicrobial strategy.201223028398
9484180.9998Phage-antibiotic combinations: a promising approach to constrain resistance evolution in bacteria. Antibiotic resistance has reached dangerously high levels throughout the world. A growing number of bacteria pose an urgent, serious, and concerning threat to public health. Few new antibiotics are available to clinicians and only few are in development, highlighting the need for new strategies to overcome the antibiotic resistance crisis. Combining existing antibiotics with phages, viruses the infect bacteria, is an attractive and promising alternative to standalone therapies. Phage-antibiotic combinations have been shown to suppress the emergence of resistance in bacteria, and sometimes even reverse it. Here, we discuss the mechanisms by which phage-antibiotic combinations reduce resistance evolution, and the potential limitations these mechanisms have in steering microbial resistance evolution in a desirable direction. We also emphasize the importance of gaining a better understanding of mechanisms behind physiological and evolutionary phage-antibiotic interactions in complex in-patient environments.202133175408
9469190.9998Reversing bacterial resistance to antibiotics by phage-mediated delivery of dominant sensitive genes. Pathogen resistance to antibiotics is a rapidly growing problem, leading to an urgent need for novel antimicrobial agents. Unfortunately, development of new antibiotics faces numerous obstacles, and a method that resensitizes pathogens to approved antibiotics therefore holds key advantages. We present a proof of principle for a system that restores antibiotic efficiency by reversing pathogen resistance. This system uses temperate phages to introduce, by lysogenization, the genes rpsL and gyrA conferring sensitivity in a dominant fashion to two antibiotics, streptomycin and nalidixic acid, respectively. Unique selective pressure is generated to enrich for bacteria that harbor the phages carrying the sensitizing constructs. This selection pressure is based on a toxic compound, tellurite, and therefore does not forfeit any antibiotic for the sensitization procedure. We further demonstrate a possible way of reducing undesirable recombination events by synthesizing dominant sensitive genes with major barriers to homologous recombination. Such synthesis does not significantly reduce the gene's sensitization ability. Unlike conventional bacteriophage therapy, the system does not rely on the phage's ability to kill pathogens in the infected host, but instead, on its ability to deliver genetic constructs into the bacteria and thus render them sensitive to antibiotics prior to host infection. We believe that transfer of the sensitizing cassette by the constructed phage will significantly enrich for antibiotic-treatable pathogens on hospital surfaces. Broad usage of the proposed system, in contrast to antibiotics and phage therapy, will potentially change the nature of nosocomial infections toward being more susceptible to antibiotics rather than more resistant.201222113912