Antibiotic-resistant pathogens are profoundly important to human health, but the environmental reservoirs of resistance determinants are poorly understood. The origins of antibiotic resistance in the environment is relevant to human health because of the increasing importance of zoonotic diseases as well as the need for predicting emerging resistant pathogens. This Review explores the presence and spread of antibiotic resistance in non-agricultural, non-clinical environments and demonstrates the need for more intensive investigation on this subject.

We present the argument that the majority of low-molecular-weight organic compounds made and secreted by microbes play roles as cell-signalling molecules in the environment. Of the large number of compounds isolated to date, only a small fraction have been shown to possess useful therapeutic antibiotic activity. However, most microbial metabolites modulate gene transcription at low concentrations, and this is proposed to be the primary effect of the compounds in the maintenance of microbial communities in the environment. Thus, microbial metabolites constitute a large collection of cell-signalling molecules that regulate gene expression in microbial populations and possibly the interactions of these populations with the surrounding organisms.

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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.