Stochastic induction of persister cells by HipA through (p)ppGpp-mediated activation of mRNA endonucleases

Bacteria produce persister cells that are tolerant to multiple antibiotics because they are hibernating in a dormant state in which the antibiotics cannot eradicate them. Persisters can thus survive after drug treatment of infections and cause relapse of disease. The formation of persister cells depends on the ubiquitous bacterial regulatory nucleotides tetra and penta-guanosine phosphate [(p)ppGpp] that activate inhibitors of cell growth. One such inhibitor, HipA (high persister protein A), is an enzyme that halts translation by inhibiting glutamyl tRNA synthetase, an essential tRNA charging enzyme. Here we show that, surprisingly, HipA-induced persistence depends on (p)ppGpp-mediated activation of yet other inhibitors of translation that catalytically degrade messenger RNA. This discovery expands our mechanistic insight into the common and important phenomenon of bacterial multidrug tolerance.