The effect is independent of Rel A functionality, specific to β-lactams, and not observed with the fluoroquinolone norfloxacin.These results refine our understanding of (p)pp Gpp's role in antibiotic tolerance and persistence and demonstrate unexpected drug interactions that lead to tolerance to bactericidal antibiotics.


Spo T is a bifunctional protein, which can both synthesize and degrade (p)pp Gpp and serves as a “hub” that integrates numerous stress signals and maintains the basal levels of the alarmone (9).(p)pp Gpp-mediated signaling is a promising target for the development of antibacterial agents since, first, this regulatory mechanism plays a central role in bacterial virulence and tolerance to antibiotics and, second, the (p)pp Gpp-mediated cytoplasmic stringent response is absent in eukaryotes (21, 22).Several compounds targeting the stringent response have been developed in recent years.Therefore, (p)pp Gpp signaling is a promising target for antibacterial drug development.Cellular synthesis and degradation of (p)pp Gpp is mediated by the members of the Rel A/Spo T homolog (RSH) protein family, which are subdivided into two classes: “long” multidomain and “short” single-domain RSHs (8).

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