Query: phage resensitization of antibiotic resistance

title: Bacteriophages targeting Acinetobacter baumannii capsule induce antimicrobial resensitization
abstract: Carbapenem resistant Acinetobacter baumannii is responsible for frequent, hard to treat and often fatal healthcare associated infections. Phage therapy, the use of viruses that infect and kill bacteria, is an approach gaining significant clinical interest to combat antibiotic resistant infections. However, a major limitation is that bacteria can develop resistance against phages. Here, we isolated phages with activity against a panel of A. baumannii strains and focused on clinical isolates AB900 and A9844 and their phages for detailed characterization. As expected, coincubation of the phages with their hosts in vitro resulted in the emergence of phage resistant bacterial mutants. Genome sequence analysis revealed that phage resistant mutants harbored loss of function mutations in genes from the K locus, responsible for the biosynthesis of the bacterial capsule. Using molecular biology techniques, phage adsorption assays, and quantitative evaluation of capsule production, we established that the bacterial capsule serves as the primary receptor for these phages. As a collateral phenotype of impaired capsule production, the phage resistant strains could not form biofilms, became fully sensitized to the human complement system, showed increased susceptibility to beta lactam antibiotics, and became vulnerable to additional phages. Finally, in a murine model of bacteremia, the phage resistant A. baumannii demonstrated a diminished capacity to colonize blood and solid tissues. This study demonstrates that phages can be used not only for their lytic activity but, if combined with a posteriori knowledge of their receptors and the mechanism of bacterial resistance, for their potential synergy with other antimicrobial agents, thus providing even broader clinical options for phage therapy.

title: Fitness Trade Offs Resulting from Bacteriophage Resistance Potentiate Synergistic Antibacterial Strategies
abstract: 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.  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.

title: Bacteriophages Contribute to the Spread of Antibiotic Resistance Genes among Foodborne Pathogens of the Enterobacteriaceae Family A Review
abstract: Foodborne illnesses continue to have an economic impact on global health care systems. There is a growing concern regarding the increasing frequency of antibiotic resistance in foodborne bacterial pathogens and how such resistance may affect treatment outcomes. In an effort to better understand how to reduce the spread of resistance, many research studies have been conducted regarding the methods by which antibiotic resistance genes are mobilized and spread between bacteria. Transduction by bacteriophages (phages) is one of many horizontal gene transfer mechanisms, and recent findings have shown phage mediated transduction to be a significant contributor to dissemination of antibiotic resistance genes. Here, we review the viability of transduction as a contributing factor to the dissemination of antibiotic resistance genes in foodborne pathogens of the Enterobacteriaceae family, including non typhoidal Salmonella and Shiga toxin producing Escherichia coli, as well as environmental factors that increase transduction of antibiotic resistance genes.

title: Phage Antibiotic Synergy is Driven by a Unique Combination of Antibacterial Mechanism of Action and Stoichiometry
abstract: The continued rise in antibiotic resistance is precipitating a medical crisis. Bacteriophage (phage) has been hailed as one possible therapeutic option to augment the efficacy of antibiotics. However, only a handful of studies have addressed the synergistic relationship between phage and antibiotics. Here, we report a comprehensive analysis of phage antibiotic interaction that evaluates synergism, additivism, and antagonism for all classes of antibiotics across clinically achievable stoichiometries. We combined an optically based real time microtiter plate readout with a matrix like heatmap of treatment potencies to measure phage and antibiotic synergy (PAS) a process we term synography. Phage antibiotic synography was performed against a pandemic drug resistant clonal group of E. coli (ExPEC) with antibiotic levels blanketing the minimum inhibitor concentration (MIC) across seven orders of viral titers. Our results suggest that, under certain conditions, phages provide an adjuvating effect by lowering the MIC for drug resistant strains. Furthermore, synergistic and antagonistic interactions are highly dependent on the mechanism of bacterial inhibition by the class of antibiotic paired to the phage, and when synergism is observed, it suppresses the emergence of resistant cells. Host conditions that simulate the infection environment, including serum and urine, suppress PAS in a bacterial growth dependent manner. Lastly, phage burst size seems to be a significant driver of synergism. Collectively, this data suggests lytic phages can resuscitate an ineffective antibiotic for previously resistant bacteria, while also synergize with antibiotics in a class dependent manner, processes that may be dampened by lower bacterial growth rates found in host environments.  therapy is a promising approach to combat the rise of multi drug resistant bacteria. Currently, the preferred clinical modality is to pair phage with an antibiotic, a practice thought to improve efficacy. However, antagonism between phage and antibiotics has been reported, the choice of phage and antibiotic is not often empirically determined, and the effect of the host factors on the effectiveness is unknown. Here, we interrogate phage antibiotic interactions across antibiotics with different mechanisms of action. Our results suggest that phage can lower the working MIC for bacterial strains already resistant to the antibiotic, is dependent on the antibiotic class and stoichiometry of the pairing, and is dramatically influenced by the host microenvironment.

title: Phage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa
abstract: Increasing prevalence and severity of multi drug resistant (MDR) bacterial infections has necessitated novel antibacterial strategies. Ideally, new approaches would target bacterial pathogens while exerting selection for reduced pathogenesis when these bacteria inevitably evolve resistance to therapeutic intervention. As an example of such a management strategy, we isolated a lytic bacteriophage, OMKO1, (family Myoviridae) of Pseudomonas aeruginosa that utilizes the outer membrane porin M (OprM) of the multidrug efflux systems MexAB and MexXY as a receptor binding site. Results show that phage selection produces an evolutionary trade off in MDR P. aeruginosa, whereby the evolution of bacterial resistance to phage attack changes the efflux pump mechanism, causing increased sensitivity to drugs from several antibiotic classes. Although modern phage therapy is still in its infancy, we conclude that phages, such as OMKO1, represent a new approach to phage therapy where bacteriophages exert selection for MDR bacteria to become increasingly sensitive to traditional antibiotics. This approach, using phages as targeted antibacterials, could extend the lifetime of our current antibiotics and potentially reduce the incidence of antibiotic resistant infections.

title: Phage Therapy in the Postantibiotic Era
abstract: Antibiotic resistance is arguably the biggest current threat to global health. An increasing number of infections are becoming harder or almost impossible to treat, carrying high morbidity, mortality, and financial cost.  Antibiotic resistance is arguably the biggest current threat to global health. An increasing number of infections are becoming harder or almost impossible to treat, carrying high morbidity, mortality, and financial cost. The therapeutic use of bacteriophages, viruses that infect and kill bacteria, is well suited to be part of the multidimensional strategies to combat antibiotic resistance. Although phage therapy was first implemented almost a century ago, it was brought to a standstill after the successful introduction of antibiotics. Now, with the rise of antibiotic resistance, phage therapy is experiencing a well deserved rebirth. Among the admittedly vast literature recently published on this topic, this review aims to provide a forward looking perspective on phage therapy and its role in modern society. We cover the key points of the antibiotic resistance crisis and then explain the biological and evolutionary principles that support the use of phages, their interaction with the immune system, and a comparison with antibiotic therapy. By going through up to date reports and, whenever possible, human clinical trials, we examine the versatility of phage therapy. We discuss conventional approaches as well as novel strategies, including the use of phage antibiotic combinations, phage derived enzymes, exploitation of phage resistance mechanisms, and phage bioengineering. Finally, we discuss the benefits of phage therapy beyond the clinical perspective, including opportunities for scientific outreach and effective education, interdisciplinary collaboration, cultural and economic growth, and even innovative use of social media, making the case that phage therapy is more than just an alternative to antibiotics.

title: Phage Therapy: Going Temperate?
abstract: Strictly lytic phages have been consensually preferred for phage therapy purposes. In contrast, temperate phages have been avoided due to an inherent capacity to mediate transfer of genes between bacteria by specialized transduction an event that may increase bacterial virulence, for example, by promoting antibiotic resistance. Now, advances in sequencing technologies and synthetic biology are providing new opportunities to explore the use of temperate phages for therapy against bacterial infections. By doing so we can considerably expand our armamentarium against the escalating threat of antibiotic resistant bacteria.

title: Strategies to Combat Multidrug Resistant and Persistent Infectious Diseases
abstract: Antibiotic failure is one of the most worrying health problems worldwide. We are currently facing an international crisis with several problematic facets: new antibiotics are no longer being discovered, resistance mechanisms are occurring in almost all clinical isolates of bacteria, and recurrent infections caused by persistent bacteria are hampering the successful treatment of infections. In this context, new anti infectious strategies against multidrug resistant (MDR) and persistent bacteria, as well as the rescue of Food and Drug Administration (FDA) approved compounds (drug repurposing) are being explored. Among the highlighted new anti infectious strategies, in this review, we focus on antimicrobial peptides, anti virulence compounds, phage therapy, and new molecules. As drugs that are being repurposed, we highlight anti inflammatory compounds, anti psychotics, anti helminthics, anti cancerous drugs, and statins.

title: Strategies to Combat Persistent Infectious Diseases
abstract: Antibiotic failure is one of the most worrying health problems worldwide. Nowadays we are facing an international crisis where several issues are involved: new antibiotics are not being discovered any longer, resistance mechanisms become spread in nearly every clinical isolate of bacteria and the appearance of recurrent infections caused by persistent bacteria complicates the overcoming of infections. In this context, it has been explored new anti infectious strategies against MDR and persistent bacteria as well as the rescue of FDA approved compounds (drug repurposing) Among the highlighted new anti infectious strategies we find anti microbial peptides, anti virulence compounds, phage therapy and new molecules. On the other hand, as drugs of repurposing that have been described, we have anti inflammatory compounds, anti psychotics, anti helmintic drugs, anti cancerous and statins.

title: A Case Series of Emergency Investigational New Drug Applications for Bacteriophages Treating Recalcitrant Multi drug Resistant Bacterial Infections: Confirmed Safety and a Signal of Efficacy
abstract: The advent and increasing prevalence of antimicrobial resistance commensurate with the absence of novel antibiotics on the horizon raises the spectre of untreatable infections. We must now grapple with infections stemming from extensively multi and pan drug resistant bacterial strains. Potential non antibiotic options to treat Multi Drug Resistant (MDR) infections include bacteriophages and there has been much fervour in resurrecting research into its clinical use. Although not subjected to the contemporary rigorous scientific standards for clinical trials, there appears to be an abundance of data purporting safety of bacteriophage therapy regardless of administration route. The US Navy and Adaptive Phage Therapeutics have taken a precision approach to development of bacteriophage therapy. Herein, as opposed to fixed phage cocktails, we exploit the quintessential example of personalized medicine by acquiring the patient's infecting isolate and identifying a phage cocktail proven to lyse the bacteria. As we prepare to execute our FDA regulated clinical phase II bacteriophage therapeutic trials in the ensuing year(s) we have engaged in numerous compassionate use eIND cases to provide potentially life saving bacteriophage treatment to patients either failing conventional antibiotic therapy due to MDR resistance, or stemming from an inability to secure definitive source control. In all eIND cases, "personalized" bacteriophage cocktails were selected which "targeted" the infecting organism. This case series reports upon 13 emergencies investigational new drug (eIND) cases whereby patients failing antibiotic therapy safely received bacteriophage mixtures (cocktails) without identifying any bacteriophagemediated adverse effects. Adjudicated microbiologic eradication of the targeted bacterial isolate was achieved in 11 cases, while 6 cases were clinically adjudicated to have achieved therapeutic efficacy defined as clinical resolution. The balance of non resolved cases was secondary to curtailed therapy (patient expiring) noninfectious mediated organ failure, or relapse of infection from biofilm mediated infections.