SUMMARY: Antibiotics have always been considered one of the wonder discoveries of the 20th century. This is true, but the real wonder is the rise of antibiotic resistance in hospitals, communities, and the environment concomitant with their use. The extraordinary genetic capacities of microbes have benefitted from man's overuse of antibiotics to exploit every source of resistance genes and every means of horizontal gene transmission to develop multiple mechanisms of resistance for each and every antibiotic introduced into practice clinically, agriculturally, or otherwise. This review presents the salient aspects of antibiotic resistance development over the past half-century, with the oft-restated conclusion that it is time to act. To achieve complete restitution of therapeutic applications of antibiotics, there is a need for more information on the role of environmental microbiomes in the rise of antibiotic resistance. In particular, creative approaches to the discovery of novel antibiotics and their expedited and controlled introduction to therapy are obligatory.

Antibiotics such as erythromycin and rifampicin, at low concentrations, alter global bacterial transcription patterns as measured by the stimulation or inhibition of a variety of promoter– lux reporter constructs in a Salmonella typhimurium library. Analysis of a 6,500-clone library indicated that as many as 5% of the promoters may be affected, comprising genes for a variety of functions, as well as a significant fraction of genes with no known function. Studies of a selection of the reporter clones showed that stimulation varied depending on the nature of the antibiotic, the promoter, and what culture medium was used; the response differed on solid as compared with liquid media. Transcription was markedly reduced in antibiotic-resistant hosts, but the presence of mutations deficient in stress responses such as SOS or universal stress did not prevent antibiotic-induced modulation. The results show that small molecules may have contrasting effects on bacteria depending on their concentration: either the modulation of bacterial metabolism by altering transcription patterns or the inhibition of growth by the inhibition of specific target functions. Both activities could play important roles in the regulation of microbial communities. These studies indicate that the detection of pharmaceutically useful natural product inhibitors could be effectively achieved by measuring activation of transcription at low concentrations in high-throughput assays using appropriate bacterial promoter–reporter constructs.

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.

Antibiotics have been used for more than 50 years and are the cornerstone of infectious disease treatment; in addition, these low-molecular-weight bioactive compounds have been applied to many other therapeutic purposes. However, there is almost no information on the evolutionary biology or ecology of naturally occurring low-molecular-weight compounds. The large number of different structural types and the extremely broad range of biological activities of organic molecules produced by microbes raise many questions concerning their roles in nature. Recent evidence for the enormous complexity of microbial populations in the environment favors the notion that the principal roles of small molecules in microbial ecology are cell–cell communication and not antibiosis.