The BIOCIDE research project - Background & Science

BACKGROUND - a short introduction

The emergence and global dissemination of antibiotic (AB) resistant bacteria has developed into a severe threat to public health, jeopardizing our ability to treat bacterial infections, cure cancer and perform advanced surgery, all of which are dependent on effective ABs.

Our extensive use of ABs and insufficient measures to prevent the spread of resistant bacteria are primary drivers of resistance. However, the external environment also contributes i) as a transmission route for several bacterial pathogens and ii) in the evolution and emergence of resistance in pathogens, as the immense diversity of environmental bacteria serves as a source for resistance genes through horizontal gene transfer.

A “one health perspective”, considering the ability of bacteria and genes to move between humans, animals and the external environment, is therefore needed to understand and efficiently manage resistance development.

In addition, co-selection from antibacterial biocides (i.e., chemicals with antibacterial properties that are not used for treating infections) can drive resistance development. These include metals and numerous organic biocides used, for example, as disinfectants in health care, as antifoulants, as preservatives, or as antibacterial agents on clothes and in household products. In addition to their specific sites of applications, biocides are widely disseminated in the environment, particularly via wastewater streams, into waterways and eventually oceans. While well justified in certain settings (e.g. disinfection in hospitals), our extensive use is likely to promote AB resistance.

There are at least two main mechanisms by which biocides may co-select for AB resistance. The first involves co-resistance, where the biocide resistance genes are present on the same, mobile genetic element (e.g., a plasmid) as the AB resistance genes. Such co-localization will indirectly select for AB resistance. The second is, referred to as cross-resistance where the biocide and the AB share a common resistance mechanism (e.g., up-regulation of efflux pumps). For both these mechanisms, exposure to biocides will directly and inevitably enrich already co-resistant strains, and thus promote their dissemination and ultimately increase transmission risks.

In addition, there is evidence that the immense genetic diversity of the environmental microbiome contributes to emergence of novel mobile AB resistance determinants in pathogens; these are less common evolutionary events but with potentially profound consequences. Here, selection from biocides could very well play a key role if cross-resistance is involved, while this is not the case for co-resistance – unless the different genes are linked from the very beginning. Therefore, understanding the relative roles of co- versus cross-resistance mechanisms in co-selection is essential to assess and manage different risk scenarios.

Moreover, the mechanism of resistance and the involved genes remain unknown for most biocides, preventing us from evaluating the link to AB resistance.

Not only do biocides have the potential to select for resistance, but also to increase horizontal gene transfer (HGT), two processes that together can exacerbate the resistance problem. Typically, effects on HGT through conjugation have only been studied using model strains, limiting generalizations. Several biocides can generate intracellular reactive oxygen species (ROS) which, in turn, provoke an SOS response leading to plasmid transfer initiation. To what extent this mechanism is conserved across bacteria is unknown.