Fig. 6. Overview of intracellular persistence regulation of S. aureus.

In vacuolar nutrient-rich compartments, persisters are metabolically active cells shielding cell wall, DNA and translation products. Under pressure of the environmental factors from the host cell, including a carbon source shift and antibiotic pressure, persisters promote a network of stress or adaptive responses displaying multiple entries. Stringent response does not show signs of activity for prolonged periods but rather contributes partly to initiate the switch to a persister phenotype through (i) post-translational modifications, contributing to an almost immediate blockade of bacterial division, and (ii) transcriptional regulation, silencing energy-consuming processes. Regulation circuits also include the cell wall stress stimulon, the SOS response, and the heat shock response. These active responses, together with a decrease in oxidative phosphorylation and in translation levels, lead to multidrug tolerance upon exposure to a single antibiotic. This stable phenotype allows bacteria to maximize the chances of long-term survival. Finally, depending on the level of stress, this state could either revert to replicative forms, or promote the evolution to resistant forms, through increased probability of mutations and horizontal gene transfer.