## 1 Introduction  
The rising of bacteria resistant to the currently available antibiotic arsenal is posing a serious threat to the way of life we have become accustomed to over the past century since [PERSON] isolated and characterized penicillin [1, 2]. If left unchecked, antimicrobial resistance (AMR), paired with the decreasing number of new antibiotics progressing through the clinical pipeline, will lead to millions of deaths each year in a few decades [3]. AMR manifests itself in stable, heritable genetic forms, as well as in lesser-known transient phenotypes that are more elusive and difficult to recognize and tackle [4]. On the other hand, antimicrobial compounds currently in the clinical phase consist mostly of derivatives of established classes, with an urgent need for drugs that address multidrug-resistant Gram-negative bacteria [3]. The search for new chemical entities, targeting non-essential pathways that play a role in both the infection process (e.g., bacterial adhesion, quorum sensing, virulence, and biofilm formation) and the insurgence of genetic resistance, is an attractive strategy for attaining new antimicrobial drugs exerting minimal selective pressure. We posit (p)ppGpp-signalling molecules (guanosine tetra- or penta-phosphate) [5] as key players in both processes [6]. Indeed, (p)ppGpp is a ubiquitous alarmone that directs bacterial adaptation to environmental changes (e.g., nutrient starvation, oxidative stress, etc.) by binding various targets involved, e.g., in nucleotide metabolism, DNA replication and repair [7], transcription [8], and translation [9, 10]. This alarmone thus has pleiotropic effects on bacterial cell physiology [11], regulating cell size, virulence, quorum sensing, and biofilm formation [12, 13, 14, 15]. In particular, its ability to downregulate cell metabolism and cell growth hints at its role in the insurgence of the bacterial non-heritable dormant phenotype called persister [16]. Persisters are transiently tolerant to antibiotic treatment (i.e., they are a form of phenotypic AMR) until they revert to the awake state and resume growth, constituting an infection reservoir that sustains chronic and recurrent infections and paves the way to the acquisition of genetic resistance [17; 18]. Over the last two decades, extensive research has revealed different molecular mechanisms leading to their formation [19], and one of them is the accumulation of (p)ppGpp together with its downstream effects. Intracellular (p)ppGpp levels are regulated by enzymes belonging to the RSH (RelA/ SpoT Homolog) superfamily [20]. These enzymes catalyze (p)ppGpp synthesis via a Mg\({}^{2+}\)-dependent pyrophosphate transfer from ATP to the 3\({}^{\prime}\)-OH group of either GDP or GTP. They also catalyze (p)ppGpp hydrolysis leading to the release of pyrophosphate (PPi) using distinct active sites in different protein domains (Figure 1a). \"Short\" RSH proteins harbor either only the synthetase (SAS, small alarmone synthetases) or hydrolase (SAH, small alarmone hydrolases) domain, respectively. \"Long\" RSH proteins contain both catalytic domains and a C-terminal regulatory domain (CTD) that activates alarmone synthesis by promoting Rel oligomerization [21] and/or upon binding to stalled ribosomes (i.e., ribosomes bound to uncharged tRNAs during aminoacid starvation) [22; 23] or favors alarmone hydrolysis by directly inhibiting the synthetase site [24]. In addition, reciprocal regulation of the two catalytic domains has been postulated with mechanisms that vary among species [25; 26; 27; 28]. The search for inhibitors of Rel enzymes synthetase activity dates back to the early 2010s, when Relacin [29] and a few other (p)ppGpp analogs [30; 31] were described by [PERSON] and co-workers. In all cases, IC\({}_{50}\) values measured against RelA (_E. coli_) and Rel from _D. radiodurans_ were estimated to be between 1 and 5 mM, with relatively low ligand efficiency and no subsequent further optimization reported. More recently, extensive efforts, including high-throughput screening (Rel\({}_{Bs}\), _B.