Riboswitches are regulatory elements modulating gene expression in response to specific metabolite binding. It has been recently reported that
riboswitch agonists may exhibit antimicrobial properties by binding to the
riboswitch domain.
Guanine riboswitches are involved in the regulation of transport and biosynthesis of
purine metabolites, which are critical for the
nucleotides cellular pool. Upon
guanine binding, these
riboswitches stabilize a 5'-untranslated
mRNA structure that causes transcription attenuation of the downstream open reading frame. In principle, any agonistic compound targeting a
guanine riboswitch could cause gene repression even when the cell is starved for
guanine.
Antibiotics binding to
riboswitches provide novel antimicrobial compounds that can be rationally designed from
riboswitch crystal structures. Using this, we have identified a
pyrimidine compound (PC1) binding
guanine riboswitches that shows bactericidal activity against a subgroup of bacterial species including well-known nosocomial pathogens. This selective bacterial killing is only achieved when guaA, a gene coding for a
GMP synthetase, is under the control of the
riboswitch. Among the bacterial strains tested, several clinical strains exhibiting multiple drug resistance were inhibited suggesting that PC1 targets a different metabolic pathway. As a proof of principle, we have used a mouse model to show a direct correlation between the administration of PC1 and the reduction of
Staphylococcus aureus infection in mammary glands. This work establishes the possibility of using existing structural knowledge to design novel
guanine riboswitch-targeting
antibiotics as powerful and selective antimicrobial compounds. Particularly, the finding of this new
guanine riboswitch target is crucial as community-acquired
bacterial infections have recently started to emerge.