Ecology and Evolutionary Biology of Hindering Phage Therapy: The Phage Tolerance vs. Phage Resistance of Bacterial Biofilms

As with antibiotics, we can differentiate various acquired mechanisms of bacteria-mediated inhibition of the action of bacterial viruses (phages or bacteriophages) into ones of tolerance vs. resistance. These also, respectively, may be distinguished as physiological insensitivities (or protections) vs. resistance mutations, phenotypic resistance vs. genotypic resistance, temporary vs. more permanent mechanisms, and ecologically vs. also near-term evolutionarily motivated functions. These phenomena can result from multiple distinct molecular mechanisms, many of which for bacterial tolerance of phages are associated with bacterial biofilms (as is also the case for the bacterial tolerance of antibiotics). The resulting inhibitions are relevant from an applied perspective because of their potential to thwart phage-based treatments of bacterial infections, i.e., phage therapies, as well as their potential to interfere more generally with approaches to the phage-based biological control of bacterial biofilms. In other words, given the generally low toxicity of properly chosen therapeutic phages, it is a combination of phage tolerance and phage resistance, as displayed by targeted bacteria, that seems to represent the greatest impediments to phage therapy’s success. Here I explore general concepts of bacterial tolerance of vs. bacterial resistance to phages, particularly as they may be considered in association with bacterial biofilms.