(p)ppGpp and the Stringent Response: An Emerging Threat to Antibiotic Therapy

In 1969, Cashel and Gallant first observed the presence of (p)ppGpp-the signaling molecule of the stringent response-in starved bacterial cells. Fifty years later, (p)ppGpp and the stringent response have emerged as essential master regulators of not only the bacterial response to stress but also almost all aspects of bacterial physiology, virulence, and immune evasion. More worryingly, a wealth of data now indicate that (p)ppGpp and stringent response activation pose a serious threat to the efficacy and clinical success of antimicrobial therapy. Here, we focus on the central role that (p)ppGpp and the stringent response play in the phenomenon of antibiotic tolerance, as well as the acquisition, development, and expression of antibiotic resistance. We review these consequences of stringent response activation in relation to the main proteins involved in (p)ppGpp production and control, in particular the complex interplay between monofunctional and bifunctional long RelA/SpoT homologues (RSHs) and small alarmone synthetases (SASs). We also review the growing evidence to suggest that there are multiple other indirect pathways of stringent response induction that can affect antibiotic efficacy. Finally, we summarize recent studies that indicate the in vivo and clinical impact of (p)ppGpp production on antibiotic treatment outcomes. We conclude by reviewing the progress to date in the search for novel therapeutics that target the stringent response.