Figure 5.

P. aeruginosa stringent response and persister formation. Stringent response is triggered by particular stresses such as amino acid and fatty acid starvation, iron/phosphor depletion and oxidative stress [e.g., reactive oxygen species (ROS)]. The (p)ppGpp alarmone is a key determinant for stringent response and it is elevated by RelA/SpoT enzymes. Generally, (p)ppGpp elevation and the PolyP (inorganic polyphosphate) and Lon protease complex interfere with normal biological processes in favor of bacterial survival via arresting metabolism, cell growth and cell division (dashed gray pathways are best understood for the E. coli model, but not or partially characterized in P. aeruginosa). In E.coli, (p)ppGpp signaling is linked to toxin (T)-antitoxin (A) system via activation of the Lon protease leading to the formation of persisters displaying dormant and antibiotic resistance phenotypes (dashed orange line). Generally, the TA complex is stable under normal conditions suppressing toxin activity and further expression of cognate genes. Upon antitoxin degradation, toxin becomes active to hinder biological processes. In the case of P. aeruginosa HigB/A, HicA/B, the toxin components perform endoribonuclease (RNase) activity on mRNA molecules. In P. aeruginosa, the (p)ppGpp alarmone is linked to the production of ROS scavengers probably via QS or RpoS regulators and Lon activity is required for biofilm formation, motility, virulence and antibiotic resistance. Furthermore, the TA system downregulates biofilm formation and virulence factor production while T3SS (type 3 secretion system) can be found upregulated. Although, the (p)ppGpp signaling, Lon protease activity and TA modules (i.e., HigB/A, HicA/B, and likely more complexes) are present in P. aeruginosa, their link to resistance to antibiotics and other stresses is poorly understood. AA, amino acids; QS, quorum sensing; RNAP, RNA polymerase. CM, cytoplasmic membrane; OM, outer membrane.