Combining forces to target bacteria

The enemy of my enemy is my friend. This proverb underlies the rationale to use viruses that specifically attack bacteria (that is bacteriophages, or phages for short) to treat bacterial infections. On paper, phages are the quintessential antibiotic. They can self-adjust their dose, they are species-specific in their target, they counter resistance through evolution, they have minimal side effects, and they can be mass-produced in a Petri dish (Loc-Carrillo and Abedon 2011). While reality is of course more complicated (see Thiel 2004 for a more sobering account), the idea of using phages to treat bacterial infections has gained momentum in the last decade owing to the global problem of resistance to chemical antibiotics (Levy and Marshall 2004). The goal is that phage therapy could complement or at times even replace chemical antibiotics. However, to attain this goal, the ecology and evolution of phage–bacteria interactions across multiple landscapes needs to be fleshed out. Two studies that make considerable headway into the complex world of phage–bacteria interactions are published in this issue of Evolutionary Applications (Escobar-Páramo et al. 2012; Zhang and Buckling 2012). The parallels between the use of phages and chemical antibiotics to treat bacterial infections are obvious. For chemical antibiotics, an informed application of evolutionary and ecological concepts, both in theory and in practice, has proven valuable in understanding the determinants for efficient treatment and helps to provide guidelines for a sustainable drug use that minimizes the probability of resistance evolution. In vitro work has demonstrated that, although resistance mutations carry a fitness cost, counter-selection in the absence of an antibiotic can fail owing to compensatory adaptations that preclude a reversion to susceptibility (Andersson and Hughes 2010). High-throughput screens have uncovered interactions between antibiotics and have lead to the surprising insight that, although certain combinations are less efficient, they may hinder the evolution of multidrug resistance in the long term (Yeh et al. 2009). Theoretical work that employs population biological principles can be applied to suggest optimal treatment strategies or to evaluate the role of factors such as hospital size or bacterial mutation rate for the evolution of drug resistance (zur Wiesch et al. 2011). However, much of our understanding of the ecology and evolution of antibiotic resistance arrived only after resistance had become extremely widespread. Phage therapy is not widely used at present in Western medicine, and by conducting the right studies now, we might be able to identify and implement treatment strategies that achieve long-term effectiveness with minimal spread of resistance – while doing some exciting fundamental evolutionary biology along the way. The range of topics related to phage therapy is vast and reads like the table of contents of an introductory textbook for ecology and evolution: host–parasite coevolution, resistance evolution, population extinction, predator-prey dynamics, virulence evolution, tri-trophic interactions, specialists versus generalists, to name a few. Zhang & Buckling and Escobar-Páramo et al. address whether the combination of phages and antibiotics can enhance treatment success. Combination therapy, the use of more than one medication to treat a single disease, is a topic that is of practical relevance, as the combined use of different antibiotics is often the last resort against multidrug-resistant pathogens nowadays. Although it has the advantage of widening the range of bacteria that are targeted and, importantly, the promise of impeding resistance evolution in bacteria, the intake of several antibiotics can place a substantial burden on the patient, which can partially offset its benefits (Kett et al. 2011). Combining phage and antibiotic therapy is therefore an interesting alternative as experience with mixtures of phage strains suggests that they put minimal additional strain on the patient (Bruttin and Brüssow 2005; Kutter et al. 2010). Then again, different antimicrobials can interact in unforeseeable ways and the combined use of phages and antibiotics must therefore be evaluated carefully, which requires experiments like the two reported here. Before discussing some of the findings, it is important to acknowledge that the experiments may seem a far stretch away from what is typically published under the title of phage therapy. Here, we are dealing with the most basic version of an infection, a bacterial monoculture in a test tube, which is passaged at regular intervals to new growth medium, and treated by adding phages or antibiotic, or both. The greater experimental control that is afforded by sacrificing the level of the patient allows more focus on specific factors, whose effect, both in isolation and in combination, can be measured much more accurately (Jessup et al. 2004). Because the individual bacterial populations (read: infections) are allowed to evolve before Evolutionary Applications ISSN 1752-4571