Bacteriophages effective against stationary cells: promising agents against antibiotic tolerant bacteria

Abstract

Bacteriophages (phages), the viruses that specifically infect and kill bacteria, are ubiquitous in the environment. Most phage-host interaction studies are performed with exponentially growing cells. In nature, however, this is not the primary pattern of growth, with bacteria often surviving in the stationary phase. These bacterial cells are typically in a slower or non-dividing state, with low metabolic activity. As phages use the metabolic machinery of the host bacteria to replicate, their efficacy against stationary cells is usually limited. Likewise, stationary cells can tolerate high doses of antibiotics, since the cellular processes commonly attacked by them are tuned down. Nonetheless, some phages have a unique ability to replicate in stationary cells. Previously, we showed that the Staphylococcus epidermidis phage SEP1 has this rare characteristic, significantly reducing the numbers of stationary cells [1]. More recently, the Pseudomonas aeruginosa phage Paride was shown to be able to replicate and lyse stationary cells in a deep dormant state [2]. In the present study, using RNA-seq, we investigated the transcriptomic profiles of both exponential and stationary cells infected with SEP1 phage to have an enlightened understanding of this phenomenon. SEP1 gradually took over the transcriptional machinery of the host in both conditions, although slowly in stationary cells. A DNA modification system was used by exponential cells, and later by stationary cells, as a defence against SEP1 infection. However, upregulation of the restriction endonuclease gene, needed for phage DNA cleavage, was not observed, with SEP1 being able to successfully replicate. In stationary cells, SEP1 was shown to activate numerous metabolic and biosynthetic processes crucial to the completion of its lifecycle, with 894 and 1319 genes upregulated at 15- and 30-min post-infection, respectively. Phages effective against stationary cells, such as SEP1, are promising agents to treat recalcitrant infections, particularly those caused by bacteria with an increased tolerance to antibiotics. Moreover, they can be used to awake stationary cells, by activating their metabolic and biosynthetic activity, and consequently to resensitize them to antibiotics.