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The spread of antibiotic-resistant pathogens requires new treatments. As the rate of development of new antibiotics has severely declined, alternatives to antibiotics must be considered in both animal agriculture and human medicine. Products for disease prevention are different from those for disease treatment, and examples of both are discussed here. For example, modulating the gut microbial community, either through feed additives or fecal transplantation, could be a promising way to prevent certain diseases; for disease treatment, non-antibiotic approaches include phage therapy, phage lysins, bacteriocins, and predatory bacteria. Interestingly, several of these methods augment antibiotic efficacy by improving bacterial killing and decreasing antibiotic resistance selection. Because bacteria can ultimately evolve resistance to almost any therapeutic agent, it is important to continue to use both antibiotics and their alternatives judiciously.
Humanity's continued success is dependent on its future ability to prevent or treat diseases. The current dissemination of antibiotic resistance genes into pathogenic bacteria calls into question the future efficacy of today's antibiotic repertoire. New antibiotics are urgently needed,[1] but so are additional approaches to preserving the value of existing antibiotics, including identifying adjuvants. Alternatives to antibiotics are also urgently needed.
more:To generate suitable alternatives, we first need to understand better why antibiotics are being overused and to define the unintended consequences. Antibiotics have multiple purposes that suggest alternatives (Table 1). Many antibiotics are used to treat specific diseases, suggesting that alternative therapies such as phages, bacteriocins, or predatory bacteria may be used similarly. Additionally, antibiotics are used for growth promotion in food-producing animals, which is not a therapeutic use. Finally, disease prevention accounts for much antibiotic use in both humans and animals, where individuals are treated, arguably, at the potential cost of selecting for antibiotic-resistant bacteria in the population. Here, we expand on our previous discussion[2] of alternatives for antibiotics. We will also discuss antibiotic adjuvants, with particular attention to therapeutic combinations of antibiotics with certain alternatives.
Phage therapy
Phages are viruses that infect bacteria. Part of the active phage lifestyle involves a lytic phase, which leads to the physical break down of host bacteria to allow escape of progeny virus. The application of lytic phages to kill pathogenic bacteria is called phage therapy (Table 1). Lytic phages of particular pathogens have been cultivated and administered to treat infections in both humans and animals.[31, 32] Although some evidence suggests that it is effective against systemic infections,[33-35] phage therapy has been primarily developed and used for accessible topical infections, such as in the paranasal sinus or on the skin.[36] In the United States, phage therapy has been developed and used for treatment of foodborne pathogens in animals[37, 38] and for biocontrol of plant pathogens,[39] while use of phage therapies for human infections is limited to mainly Eastern European countries.[34] Currently, regulatory agencies in Western countries pose a potentially great obstacle to clinical use of phage therapy in humans, but one suggestion is to use the annual influenza vaccine approval process as a model.[36]
Phage therapy is much more specific to the targeted bacteria than is antibiotic therapy, and thus unintended effects on nontarget bacteria are minimal. However, empirical studies suggest that phage specificity for particular bacteria ranges from very narrow to broad, and is dependent on the phage titer,[40] so measuring the collateral effects of phage therapy on commensal bacteria is important. Another critical factor to consider is the possible development of bacterial resistance to phages, which, on the one hand, is a short-term problem for treatment (i.e., lost infectivity of the phage to a specific bacterial target) but, on the other hand, because the cellular modifications associated with phage resistance can also pose a long-term fitness cost to the host bacterium (which could lead to altered microbiota).[41, 42] Resistance development can be mitigated by employing a cocktail of multiple phages rather than a single one.[38] Despite the advantages of specificity for reduced resistance development, specificity can pose a technical limitation to the broad implementation of phage therapy, such as the challenge of devising a single phage therapy to treat different pathogenic subspecies among individual humans or animals.[43]
One way to tailor the therapeutics of phage therapy is to engineer the activities of specific subunits of a phage.[44] For example, endolysins are produced by phages to cleave bonds in the peptidoglycan layer, which permeabilizes the cell wall and causes lysis. The group of endolysins encompass a diverse array of activities and targets, with at least five different families targeting various bonds in the peptidoglycan matrix.[45] This diversity allows for bioengineering to expand substrate and species specificity in a single phage therapeutic, both engineered activities being advantageous for reducing the potential for resistance development (Table 1).[46] One challenge posed by endolysins is that they are predominantly effective against Gram-positive bacteria because of the exposed peptidoglycan layer of these bacteria; however, recent progress has been made in characterizing and developing endolysins against Gram-negative pathogens.[47-49] Other types of peptidoglycan hydrolases, including exolysins, offer additional therapeutic potential.
http://onlinelibrary.wiley.com/doi/10.1111/nyas.12468/full
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