Antibiotic resistance is a threat to human and animal health worldwide, and key measures are required to reduce the risks posed by antibiotic resistance genes that occur in the environment. These measures include the identification of critical points of control, the development of reliable surveillance and risk assessment procedures, and the implementation of technological solutions that can prevent environmental contamination with antibiotic resistant bacteria and genes. In this Opinion article, we discuss the main knowledge gaps, the future research needs and the policy and management options that should be prioritized to tackle antibiotic resistance in the environment.

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It has been widely assumed that the ecological function of antibiotics in nature is fighting against competitors. This made them a good example of the Darwinian struggle-for-life in the microbial world. Based on this idea, it also has been believed that antibiotics, even at subinhibitory concentrations, reduce virulence of bacterial pathogens. Herein, using a combination of genomic and functional assays, we demonstrate that specific antibiotics (namely tobramycin, tetracycline, and norfloxacin) at subinhibitory concentrations trigger expression of determinants influencing the virulence of the major opportunistic bacterial pathogen Pseudomonas aeruginosa. All three antibiotics induce biofilm formation; tobramycin increases bacterial motility, and tetracycline triggers expression of P. aeruginosa type III secretion system and consequently bacterial cytotoxicity. Besides their relevance in the infection process, those determinants are relevant for the ecological behavior of this bacterial species in natural, nonclinical environments, either by favoring colonization of surfaces (biofilm, motility) or for fighting against eukaryotic predators (cytotoxicity). Our results support the notion that antibiotics are not only bacterial weapons for fighting competitors but also signaling molecules that may regulate the homeostasis of microbial communities. At low concentrations, they can even be beneficial for the behavior of susceptible bacteria in natural environments. This is a complete change on our vision on the ecological function of antibiotics with clear implications both for the treatment of infectious diseases and for the understanding of the microbial relationships in the biosphere. environment ͉ hormesis ͉ signals ͉ antibiotics ͉ Pseudomonas aeruginosa

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Bacterial multidrug efflux pumps are antibiotic resistance determinants present in all microorganisms. With few exceptions, they are chromosomally encoded and present a conserved organization both at the genetic and at the protein levels. In addition, most, if not all, strains of a given bacterial species present the same chromosomally-encoded efflux pumps. Altogether this indicates that multidrug efflux pumps are ancient elements encoded in bacterial genomes long before the recent use of antibiotics for human and animal therapy. In this regard, it is worth mentioning that efflux pumps can extrude a wide range of substrates that include, besides antibiotics, heavy metals, organic pollutants, plant-produced compounds, quorum sensing signals or bacterial metabolites, among others. In the current review, we present information on the different functions that multidrug efflux pumps may have for the bacterial behaviour in different habitats as well as on their regulation by specific signals. Since, in addition to their function in non-clinical ecosystems, multidrug efflux pumps contribute to intrinsic, acquired, and phenotypic resistance of bacterial pathogens, the review also presents information on the search for inhibitors of multidrug efflux pumps, which are currently under development, in the aim of increasing the susceptibility of bacterial pathogens to antibiotics.

Antibiotics are among the most valuable compounds used for fighting human diseases. Unfortunately, pathogenic bacteria have evolved towards resistance. One important and frequently forgotten aspect of antibiotics and their resistance genes is that they evolved in non-clinical (natural) environments before the use of antibiotics by humans. Given that the biosphere is mainly formed by micro-organisms, learning the functional role of antibiotics and their resistance elements in nature has relevant implications both for human health and from an ecological perspective. Recent works have suggested that some antibiotics may serve for signalling purposes at the low concentrations probably found in natural ecosystems, whereas some antibiotic resistance genes were originally selected in their hosts for metabolic purposes or for signal trafficking. However, the high concentrations of antibiotics released in specific habitats (for instance, clinical settings) as a consequence of human activity can shift those functional roles. The pollution of natural ecosystems by antibiotics and resistance genes might have consequences for the evolution of the microbiosphere. Whereas antibiotics produce transient and usually local challenges in microbial communities, antibiotic resistance genes present in gene-transfer units can spread in nature with consequences for human health and the evolution of environmental microbiota that are largely ignored.

Multidrug efflux pumps have emerged as relevant elements in the intrinsic and acquired antibiotic resistance of bacterial pathogens. In contrast with other antibiotic resistance genes that have been obtained by virulent bacteria through horizontal gene transfer, genes coding for multidrug efflux pumps are present in the chromosomes of all living organisms. In addition, these genes are highly conserved (all members of the same species contain the same efflux pumps) and their expression is tightly regulated. Together, these characteristics suggest that the main function of these systems is not resisting the antibiotics used in therapy and that they should have other roles relevant to the behavior of bacteria in their natural ecosystems. Among the potential roles, it has been demonstrated that efflux pumps are important for processes of detoxification of intracellular metabolites, bacterial virulence in both animal and plant hosts, cell homeostasis and intercellular signal trafficking.

Integrated antibiotic resistance (AR) surveillance is one of the objectives of the World Health Organization global action plan on antimicrobial resistance. Urban wastewater treatment plants (UWTPs) are among the most important receptors and sources of environmental AR. On the basis of the consistent observation of an increasing north-to-south clinical AR prevalence in Europe, this study compared the influent and final effluent of 12 UWTPs located in seven countries (Portugal, Spain, Ireland, Cyprus, Germany, Finland, and Norway). Using highly parallel quantitative polymerase chain reaction, we analyzed 229 resistance genes and 25 mobile genetic elements. This first trans-Europe surveillance showed that UWTP AR profiles mirror the AR gradient observed in clinics. Antibiotic use, environmental temperature, and UWTP size were important factors related with resistance persistence and spread in the environment. These results highlight the need to implement regular surveillance and control measures, which may need to be appropriate for the geographic regions.