Understanding the Mechanisms That Drive Phage Resistance in Staphylococci to Prevent Phage Therapy Failure

Despite occurring at the microscopic scale, the armed race between phages and their bacterial hosts involves multiple mechanisms, some of which are just starting to be understood. On the one hand, bacteria have evolved strategies that can stop the viral infection at different stages (adsorption, DNA injection and replication, biosynthesis and assembly of the viral progeny and/or release of the newly formed virions); on the other, phages have gradually evolved counterattack strategies that allow them to continue infecting their prey. This co-evolutionary process has played a major role in the development of microbial populations in both natural and man-made environments. Notably, understanding the parameters of this microscopic war will be paramount to fully benefit from the application of phage therapy against dangerous, antibiotic-resistant human pathogens. This review gathers the current knowledge regarding the mechanisms of phage resistance in the Staphylococcus genus, which includes Staphylococcus aureus, one of the most concerning microorganisms in terms of antibiotic resistance acquisition. Some of these strategies involve permanent changes to the bacterial cell via mutations, while others are transient, adaptive changes whose expression depends on certain environmental cues or the growth phase. Finally, we discuss the most plausible strategies to limit the impact of phage resistance on therapy, with a special emphasis on the importance of a rational design of phage cocktails in order to thwart therapeutic failure.