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 res...

The evolution of antibiotic resistance in bacteria is a global concern and the use of bacteriophages alone or in combined therapies is attracting increasing attention as an alternative. Evolutionary theory predicts that the probability of bacterial resistance to both phages and antibiotics will be lower than to either separately, due for example to fitness costs or to trade-offs between phage resistance mechanisms and bacterial growth. In this study, we assess the population impacts of either individual or combined treatments of a bacteriophage and streptomycin on the nosocomial pathogen Pseudomonas aeruginosa. We show that combining phage and antibiotics substantially increases bacterial control compared to either separately, and that there is a specific time delay in antibiotic introduction independent of antibiotic dose, that minimizes both bacterial density and resistance to either antibiotics or phage. These results have implications for optimal combined therapeutic approaches.

Antibiotic resistance evolution in bacteria indicates that one of the challenges faced by phage therapy is that, sooner or later, bacteria will evolve resistance to phages. Evidently, this is the case of every known antimicrobial therapy, but here this is also part of a ubiquitous natural process of co-evolution between phages and bacteria. Fundamental evolutionary studies hold some clues that are crucial to limit the problematic process of bacterial resistance during phage applications. First, I discuss here the importance of defining evolutionary and ecological factors influencing bacterial resistance and phage counter-defense mechanisms. Then, I comment on the interest of determining the co-evolutionary dynamics between phages and bacteria that may allow for selecting the conditions that will increase the probability of therapeutic success. I go on to suggest the varied strategies that may ensure the long-term success of phage therapy, including analysis of internal phage parameters and personalized treatments. In practical terms, these types of approaches will define evolutionary criteria regarding how to develop, and when to apply, therapeutic phage cocktails. Integrating this perspective in antimicrobial treatments, such as phage therapy, is among the necessary steps to expand its use in the near future, and to ensure its durability and success.

RNA silencing participates in several important functions: from the regulation of cell metabolism and organism development to sequence-specific antiviral defense. Most plant viruses have evolved proteins that suppress RNA silencing and that in many cases are multifunctional. Tobacco etch potyvirus (TEV) HC-Pro protein suppresses RNA silencing and participates in aphid-mediated transmission, polyprotein processing, and genome amplification. In this study, we have generated 28 HC-Pro amino acid substitution mutants and quantified their capacity as suppressors of RNA silencing in a transient expression assay. Most mutations either had no quantitative effect or completely abolished silencing suppression (10 in each class), 3 caused a significant decrease in the activity, and 5 significantly increased it, revealing an unexpected high frequency of mutations conferring hypersuppressor activity. A representative set of the mutant alleles, containing both hypo- and hypersuppressors, was further analyzed for their effect on TEV accumulation and the strength of induced symptoms. Whereas TEV variants with hyposuppressor mutants were far less virulent than wild-type TEV, those with hypersuppressor alleles induced symptoms that were not more severe than those characteristic of the wild-type virus, suggesting that there is not a perfect match between suppression and virulence.