The
nucleotide alarmone (
p)ppGpp, signaling the stringent response, is known for more than 5 decades. The cellular turnover of the
alarmone is regulated by RelA/SpoT homolog (RSH) superfamily of
enzymes. There are long RSHs (RelA, SpoT, and Rel) and short RSHs [small
alarmone synthetases (SAS) and small
alarmone hydrolases (SAH)]. Long RSHs are multidomain
proteins with (
p)ppGpp synthesis, hydrolysis, and regulatory functions. Short RSHs are single-domain
proteins with a single (
p)ppGpp synthesis/hydrolysis function with few exceptions having two domains. Mycobacterial RelZ is a dual-domain SAS with
RNase HII and the (
p)ppGpp synthetase activity. SAS is known to impact multiple cellular functions independently and in accordance with the long RSH. Few SAS in bacteria including RelZ synthesize pGpp, the third small
alarmone, along with the conventional (
p)ppGpp. SAS can act as an
RNA-binding protein for the negative allosteric inhibition of (
p)ppGpp synthesis. Here, we initially recap the important features and molecular functions of different SAS that are previously characterized to understand the obligation for the "
alarmone pool" produced by the long and short RSHs. Then, we focus on the RelZ, especially the combined functions of
RNase HII and (
p)ppGpp synthesis from a single
polypeptide to connect with the recent findings of SAS as an
RNA-binding protein. Finally, we conclude with the possibilities of using single-stranded
RNA (ssRNA) as an additional therapeutic strategy to combat the
persistent infections by inhibiting the redundant (
p)ppGpp synthetases.