Antibiotics as Signal Molecules

Antibiotics have been extensively used in the treatment of infectious diseases. The lethality of these compounds has been exploited in clinical and laboratory approaches and their specific targets in bacterial physiology elucidated. However, along with this development of drugs has come the problem of increasing resistance in microbes, resulting in dramatically reduced therapeutic effectiveness 1. Pathogenic microbes have rapidly evolved efficient mechanisms of resistance, including increased efflux, enzymatic inactivation, target modification, or biofilm formation 2. The concentrations of these molecules required to achieve an antimicrobial effect are likely extremely high compared to the concentrations in which these molecules can be found in natural environments. While we know their effect at lethal concentrations, the activities of these molecules at concentrations below the inhibitory limit needs deeper investigation 3. The findings of the nineteenth-century pharmacologist Hugo Schulz, who noted that certain disinfectants could have stimulatory effect on yeast growth at low concentrations, could be considered the first evidence that the action of an antimicrobial can cause a differential response depending on the concentration. His observation was the first example of what it would be later called hormesis. This term was coined by Chester Southam and John Ehrlich in the mid-1920s and it is used to refer to the ability of certain molecules to induce diverse responses depending on the concentration used 3. The vast amount of information related to the lethal concentration of antibiotics, targets, or side effects, contrasts dramatically with the relatively few studies focused on their effect at concentrations below the MIC (minimal inhibitory concentration). As pointed by Davies, only a small fraction of natural products that have antimicrobial activity have been extensively studied, and their role in natural settings is poorly understood. Thus it is possible that many of these molecules formerly considered antibiotics might have a different function in nature. It is now believed that many of these compounds might act as signaling molecules that modulate gene expression in microbial populations, or physiological functions such as motility, pigmentation, and production of metabolites, and thus facilitate inter- and intra-species communication 4. This fundamental lack of understanding may be rooted in our conception of the microbial world as single and separated species, as they are usually studied under laboratory conditions. However, in nature, each niche is complex, and to different extents, variable in microbial community composition 5,6–8. Therefore it is conceivable that molecules fluctuate in concentration and diversity, thus facilitating communication among species 9. Many interesting lines of research are currently focused on understanding how some antibiotics may affect, either positively or negatively, cell-cell communication systems, and the physiological responses that are affected as a result. In some cases, natural products can influence the ability of bacteria to transition from a planktonic state to complex multicellular aggregates attached to surfaces known as biofilms. Cells in bioflms are encased in an extracellular matrix which can serve as a barrier for antibiotics 10. One example is the biofilm produced by the gram-negative pathogen, Pseudomonas aeruginosa, which is resistant to antibiotics produced by gram-positive competitors 11. Studies on many model microorganisms from the genera Bacillus, Streptomyces, and Pseudomonas are shedding new light on the fascinating world of cell signaling and communication in microbial world 5,12,13. We will discuss in this review several examples of the dual functions of some well-known antibiotics, including those that when used at sub-inhibitory concentrations (SIC) promote an interesting response in bacterial populations and the ecological implications of such varied responses. Also, the role of other naturally synthesized antibiotics will be discussed in the context of cell communication in natural environments, including one of the most exploited environmental niches for antibiotic discovery, the soil.