Role of (p)ppGpp in antibiotic resistance, tolerance, persistence and survival in Firmicutes

Abstract

The stringent response and its signaling nucleotides pppGpp and ppGpp have been subject of intense research since the discovery of (p)ppGpp in 1969. Recent studies have revealed that the downstream events that follow (p)ppGpp accumulation vary among species. Consequently, the stringent response as initially characterized in Escherichia coli largely differs from the response in Firmicutes (Bacillota), wherein synthesis and degradation of the messengers (p)ppGpp is orchestrated by the bifunctional Rel enzyme with synthetase and hydrolase activity and the two synthetases SasA/RelP and SasB/RelQ. Here we will summarize recent studies supporting the role of (p)ppGpp in the development of antibiotic resistance and tolerance as well as survival under adverse environmental conditions in Firmicutes. We will also discuss the impact of elevated (p)ppGpp levels on the development of persister cells and establishment of persistent infections. (p)ppGpp levels are usually tightly controlled to allow optimal growth under non-stressed conditions. Upon the onset of certain ‘stringent conditions’ the sudden increase in (p)ppGpp levels limits growth while exerting protective effects. In Firmicutes, the (p)ppGpp mediated restriction of GTP accumulation is one major mechanism of protection and survival under stresses such as antibiotic exposure. An overview of the contribution of the stringent response and (p)ppGpp to the development of antibiotic resistance, tolerance and persistence as well as to survival under adverse environmental conditions in Firmicutes.

Coordinated regulation of osmotic imbalance by c-di-AMP shapes ß-lactam tolerance in Group BStreptococcus

“…In addition, cdA likely inhibits the RCK_C domain containing protein EriC, a chloride channel protein necessary to reestablish the ionic balance after osmolyte uptake 27 . Lastly, binding of cdA to the small CBS domain protein CbpB abolishes the CbpB-Rel allosteric interaction leading to decreased (p)ppGpp synthase activity 38 , which is a conserved mechanism of antibiotic tolerance 58,59 .…”

Tale of Twin Bifunctional Second Messenger (p)ppGpp Synthetases and Their Function in Mycobacteria

“…It describes the ability of bacteria to survive by slowing down metabolic cascades, and it is often referred to as phenotypic resistance. , Antibiotic tolerance and persistence may lead to the emergence of antibiotic resistance as persistence provides a viable group of cells with time in which the resistant mutants can emerge by de novo chromosomal mutations or horizontal gene transfer. , A recent de novo study demonstrated that M. tuberculosis cells exposed to lethal concentrations of antibiotics would generate antibiotic tolerance, and such cells could become resistant to the same antibiotics . Most antibiotics target active metabolic processes including replication and translation, and decreased growth rate may leads to multidrug tolerance . The stringent response has also been implicated in the downregulation of the genes required for growth in bacteria, including ribosome and cell wall synthesis. , The inhibition of growth by stringent response indirectly protects the cells from stress and antibiotics that usually target pathways involved in growth and metabolism.…”

“… 82 Most antibiotics target active metabolic processes including replication and translation, and decreased growth rate may leads to multidrug tolerance. 83 The stringent response has also been implicated in the downregulation of the genes required for growth in bacteria, including ribosome and cell wall synthesis. 84 , 85 The inhibition of growth by stringent response indirectly protects the cells from stress and antibiotics that usually target pathways involved in growth and metabolism.…”

Light-Based Anti-Biofilm and Antibacterial Strategies

“…The stringent response in persister cells is initiated through activation of the alarmone guanosine-5′-(tri)diphosphate-3′-diphosphate ((p)ppGpp), altering cellular physiology through transcriptional changes in populations with low metabolic activity, which consequently relocate cellular resources and ensure the survival of the bacterium [ 84 ]. Most antibiotics target active metabolic processes, and with this immediate shut-down of metabolism and growth, high levels of (p)ppGpp make bacteria insensitive to the actions of antibiotics [ 85 ]. A stringent response makes Pseudomonas aeruginosa biofilms tolerant to fluoroquinolones, meropenem, and gentamycin by preventing the accumulation of reactive oxidative species (ROS), which is considered a common mechanism by which antibiotics kill bacteria [ 86 , 87 ].…”