Three gene products govern (p)ppGpp production by Streptococcus mutans

The current dogma implicating RelA as the sole enzyme controlling (p)ppGpp production and degradation in Gram-positive bacteria does not apply to Streptococcus mutans. We have now identified and characterized two genes, designated as relP and relQ, encoding novel enzymes that are directly involved in (p)ppGpp synthesis. Additionally, relP is co-transcribed with a two-component signal transduction system (TCS). Analysis of the (p)ppGpp synthetic capacity of various mutants and the behaviour of strains lacking combinations of the synthetase enzymes have revealed a complex regulon and fundamental differences in the way S. mutans manages alarmone production compared with bacterial paradigms. The functionality of the RelP and RelQ enzymes was further confirmed by demonstrating that expression of relP and relQ restored growth of a (p)ppGpp⁰Escherichia coli strain in minimal medium, SMG and on medium containing 3-amino-1,2,4-triazole, and by demonstrating (p)ppGpp production in various complemented mutant strains of E. coli and S. mutans. Notably, RelQ, and RelP and the associated TCS, are harboured in some, but not all, pathogenic streptococci and related Gram-positive organisms, opening a new avenue to explore the variety of strategies employed by human and animal pathogens to survive in adverse conditions that are peculiar to environments in their hosts.