Dual Effects of MLS Antibiotics Transcriptional Modulation and Interactions on the Ribosome

The macrolide-lincosamide-streptogramin (MLS) antibiotics are an important group of translation inhibitors that act on the 50S ribosome. We show that, at subinhibitory concentrations, members of the MLS group modulate specific groups of bacterial promoters, as detected by screening a library of promoter-luxCDABE reporter clones of Salmonella enterica serovar Typhimurium. The patterns of transcription permit identification of classes of promoters having differential responses to antibiotics of related structure and mode-of-action; studies of antibiotic synergy or antagonism showed that eukaryotic translation inhibitors may act on the 50S ribosome. The mechanism of transcriptional modulation is not known but may involve bacterial stress responses and/or the disturbance and subsequent compensation of metabolic networks as a result of subtle interference with ribosome function. Transcriptional patterns detected with promoter-lux clones provide a novel approach to antibiotic discovery and mode-of-action studies.