Should bacteriophages be included in the environmental surveillance of risks associated with antimicrobial resistance?

This latter process is driven by bacteriophages (or simply phages), which can insert their own or foreign DNA into bacterial cells. Although discovered more than 60 years ago, the contribution of transduction to bacterial horizontal gene transfer is still a worthy topic for further research. In fact, in addition to the two widely known mechanisms (generalised and specialised), a new transduction mechanism has recently been described in temperate phages of Staphylococcus aureus, called lateral transduction, in which very long fragments of bacterial chromosome are transferred to another bacterium. It should also be noted that phage are the most abundant and diverse biological entities on Earth, with an estimated total population of 1031, which is even higher than the number of stars in the observable universe.

Their high abundance and the fact that phage are present in virtually all ecosystems make them one of the most efficient vehicles for moving genetic material between bacterial cells. So, this raises the following questions: to what extent does phage-mediated transduction contribute to antimicrobial resistance, and what cost-effective interventions should be implemented to mitigate this risk? Unfortunately, there are no easy answers to such questions. Most of the available information is limited to experimental conditions, especially in phage infecting clinically relevant bacteria. However, the development of cutting-edge genomic and metagenomic approaches is leading to significant advances in our understanding of the contribution of phage to bacterial ecology and evolution.

In an effort to investigate whether phage harbour antibiotic resistance genes (ARGs), our research team carried out a comprehensive analysis of several viromes from different habitats. Our results showed that while human-associated viromes rarely carry ARGs, viromes from non-human sources contain a large reservoir of such genes, especially in phage from aquatic environments. Moreover, two novel β-lactamases have recently been identified via functional assays of ARGs recovered from urban surface water viromes, which is the first evidence of functionally active ARGs transferred by phage. These findings suggest that phage could play a more important role in the acquisition, maintenance and spread of antimicrobial resistance than previously expected.

Given that aquatic ecosystems are not exempt from the impact of antimicrobial resistance, proper management practices should be adopted to tackle this global phenomenon. And why should phage be considered here? Several studies have demonstrated that a diverse mixture of antibiotics and other pollutants, their metabolites and resistant bacteria may reach aquatic ecosystems through treated and untreated sewage, hospital waste, aquaculture discharges and agricultural runoff. Consequently, aquatic environments may provide ideal selective and ecological conditions for horizontal gene transfer among bacterial species. Although several wastewater treatment technologies and combined disinfection methods have been implemented to reduce the microbial load, phage are usually resistant to these treatments due to their protection inside the protein capsid. In this sense, our research team has compiled a wealth of information about how phage, ARGs and disinfection practices intersect. Our work highlights that several barriers exist for the water sector in relation to antimicrobial resistance. Considering that the water sector already faces several long-term sustainability issues, actions and investments to tackle antimicrobial resistance should be implemented without further financially burdening the sector. Our work has also suggested some promising technologies to remove both ARGs and phage, but this still requires an extensive analysis of how these could be implemented at large scale.

Although further studies are needed to understand the factors and mechanisms involved in the emergence and spread of antimicrobial resistance, the contribution of phage to environmental antibiotic resistance should not be underestimated. Such knowledge will provide new avenues to develop effective strategies for reducing the impact of antimicrobial resistance on public and environmental health.