Emerging and divergent roles of pyrophosphorylated nucleotides in bacterial physiology and pathogenesis

Abstract

Bacteria inhabit diverse environmental niches and consequently must modulate their metabolism to adapt to stress. The nucleotide second messengers guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp) (collectively referred to as (p)ppGpp) are essential for survival during nutrient starvation. (p)ppGpp is synthesized by the RelA-SpoT homologue (RSH) protein family and coordinates the control of cellular metabolism through its combined effect on over 50 proteins. While the role of (p)ppGpp has largely been associated with nutrient limitation, recent studies have shown that (p)ppGpp and related nucleotides have a previously underappreciated effect on different aspects of bacterial physiology, such as maintaining cellular homeostasis and regulating bacterial interactions with a host, other bacteria, or phages. (p)ppGpp produced by pathogenic bacteria facilitates the evasion of host defenses such as reactive nitrogen intermediates, acidic pH, and the complement system. Additionally, (p)ppGpp and pyrophosphorylated derivatives of canonical adenosine nucleotides called (p)ppApp are emerging as effectors of bacterial toxin proteins. Here, we review the RSH protein family with a focus on its unconventional roles during host infection and bacterial competition.

Survival of Escherichia coli after high-antibiotic stress is dependent on both the pregrown physiological state and incubation conditions

“…This indicates that the deletion of relA makes the cell slightly more vulnerable to antibiotic treatment in some conditions and considerably more vulnerable to ciprofloxacin in N-limited conditions. The increased vulnerability of the ΔrelA cells was not unexpected due to the known role of RelA-dependent synthesis of (p)ppGpp during the stringent response and amino acid starvation (Chau et al, 2021). These results are in line with other studies on survival after high doses of ampicillin, gentamicin, or norfloxacin, even though the assay conditions differ from the ones used here (Hansen et al, 2008;Kudrin et al, 2017;Liu et al, 2017;Sinha et al, 2019;Svenningsen et al, 2019).…”

“…N-free, HAS medium lacking nitrogen; Exp, exponential phase; Clim, carbon-limited stationary phase; Nlim, nitrogen-limited stationary phase. 4A; Chau et al, 2021). On the other hand, there was a distinct separation along PC1 with the ΔrelA most distant from the exponential cells for the stationary grown cultures.…”

“…In this context, it was interesting to study HAS-survival in an E. coli ΔrelA mutant impaired in its nutrient stress response (Chau et al, 2021;Svenningsen et al, 2021). (p)ppGpp synthesis is shown to be considerably reduced in the ΔrelA mutant in both Nlim and Clim…”

Protein–Ligand Interactions in Scarcity: The Stringent Response from Bacteria to Metazoa, and the Unanswered Questions

“…Like all second messengers, the stress-generated (p)ppGpp regulates a bewildering number of signaling steps and pathways, affecting multiple aspects of cellular metabolism and behavior, reported and reviewed by many leading investigators over the years [ 1 , 31 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ]. The majority of the effects can be explained by the need for activation of emergency functions required for survival during stress, while conserving the cellular resources by shutting down housekeeping genes that are dispensable for the short term.…”

Awakening sleeper cells: a narrative review on bacterial magic spot synthetases as potential drug targets to overcome persistence

“…When compared to bisphosphonate, relacin had lower hydrophilicity and showed in vivo action against B. subtilis which was a considerable improvement. Still its potency was not substantial (IC 50 = 200 µM) and had no biological activity against Gram-negative microbes (Chau et al 2021 ). The quest for more potent molecules started by keeping either relacin or ppGpp as the base molecule.…”