In this issue of Cell Chemical Biology, Wang et al. (2017) examine the effect of the novel synthetic molecule ribocil-C and the natural compound roseoflavin in Gram-positive pathogens. In methicillin-resistant Staphylococcus aureus (MRSA), ribocil-C and roseoflavin target two autonomous riboswitches simultaneously, thereby inhibiting de novo synthesis and uptake of riboflavin.