Executive summary

Antimicrobial resistance (AMR) is a growing issue within water and the environment. Natural Capital Approaches (NCA) provide an opportunity to integrate ecosystem-oriented management with economic decision making and development in order to formulate an action plan for AMR within water catchment management. NCA may be used as a remediation strategy for the removal of driving agents (clinical antimicrobials, metals, biocides) from water and the environment. However, for this to occur, the method must be tailored to the specific driving agent intending to be removed, rather than aiming for a ‘one solution fits all’ approach.

Whilst plenty of research exists regarding the discovery of antibiotics as an emerging contaminant within water supplies, there is a significant lack of research regarding the occurrence of other clinically used antimicrobials such as antifungals or antivirals. It is a common misconception that reducing the use of clinical antimicrobials will solve AMR as it has long been known that AMR occurrence is continuing to rise exponentially within the developed world despite drastic reductions in administration of clinical antimicrobials. It is highly possible that the daughter products from biodegradation of clinically used antimicrobials continue to drive AMR, yet there is little research on the significance of what this role may be. Until further research has been completed; it is not recommended to use a NCA as an action plan for removing clinical antimicrobials from the water and environment for risk of accentuating the issue and creating a reservoir of antimicrobial daughter products of unknown effect within the environment.

As a result of both co- and cross-resistance, heavy metals are a key driving agent of AMR within the environment. High concentrations of metals enter the water environment dominantly as a result of the agricultural/aquiculture industry and industrial effluent. Metals do not biodegrade, resulting in the high concentrations accumulating within aquatic sediments etc. which continue to drive AMR on extremely long time scales. This report has concluded that, with increased awareness , NCA could be potentially effective in remediating against the concentration of heavy metals driving AMR. NCA for AMR could easily be integrated into current projects within Mott MacDonald. This report has identified that interception of pathways between agricultural runoff and surface water bodies, or between aquaculture farms and downstream water bodies, would be the most effective use of NCA for preventing the catchment-wide occurrence and circulation of AMR genes. One of the best examples of where this may be applied is within drainage ditches (both road-side and field-side).

For precautionary reasons; a more detailed assessment of the role of the natural environment in the occurrence and dissemination of AMR is crucial prior to any implementation of the NCA concept can take place.

1 Background

1.1 Scope

The Natural Capital Approach (NCA) is a means for identifying and quantifying natural resources and associated ecosystem services that may help integrate ecosystem-orientated management and economic decision making and development.

The NCA concept is gaining considerable support globally for devising policies that reconcile environmental and economic imperatives as well as aligning policy making to sustainable development. One of the best examples of NCA being successfully used within water catchment management is the remediation of acid mine drainage and flood management through methods such as the creation of wetlands or riparian zones.

The Mott MacDonald Professional Excellence and Innovation Fund has provided a grant to an initiative to work across different sectors of the company on antimicrobial resistance (AMR), of which this report is one output. The report presents a summary of aspects of AMR in water and the environment, specifically addressing whether a natural capital management approach may be used to address the issue of AMR .

1.2 What is antimicrobial resistance?

Antimicrobials are defined as any natural or synthetic substance that kills or inhibits the growth of micro-organisms such as bacteria, fungi and algae. The minimum inhibitory concentration (MIC) is the lowest concentration of an antimicrobial required to inhibit the growth of a given strain of micro-organism. If the MIC value is greater than a defined epidemiological cut off value, then the strain is defined as being antimicrobial resistant (Burnham et al 2017).

1.2.1 Mechanisms of resistance

There are three mechanisms by which micro-organisms develop resistance to an antimicrobial agent:

1. Alteration or protection of antimicrobial target e.g. by DNA-binding proteins (e.g. quinolone resistance genes - Qnr)

2. Decreased accumulation of antimicrobial agent within the micro-organism: either by reduced penetration (e.g. gram-negative bacteria have an outer membrane preventing penetration of penicillin) or by increased efflux (excretion) of the anti-microbial agent out of the micro-organism.

3. Enzymatic modification i.e. secretion of enzymes capable of modifying or destroying the antimicrobial before it reaches its target. Such mechanisms occur within both clinical and non-clinical environments in response to evolutionary selection pressures (Holmes et al 2015).

1.2.2 Dissemination of AMR

Horizontal gene transfer (HGT) is one of the primary methods of concern with regards to the dissemination of antimicrobial resistance within a population. HGT may occur between all unicellular organisms including viruses, bacteria, fungi etc. (Burnham et al 2017). HGT occurs via the following three mechanisms:

● TRANSFORMATION: micro-organisms take up and incorporate free DNA from the environment and combine it with their own.

● TRANSDUCTION: viruses (bacteriophages, mycophages) mediate the transfer of DNA between micro-organisms via transduction. DNA is packaged from the donor into the virus than transferred to the next recipient of the virus.

● CONJUGATION: A sex pilus forms between two bacterial cells through which a plasmid of DNA is transferred from one micro-organism to another (Holmes et al 2015).

Another important mechanism of dissemination is the colonial expansion of strains where a point mutation occurs. Point mutations within genes may provide resistance to certain compounds, particularly when the mutation occurs on loci involved in protein biosynthesis. Expansion of the colony containing these genes results in the development of resistant strains of micro-organisms which will rapidly out-compete susceptible strains; such as is the case with healthcare-associated MRSA clinically resistant strains. (Dean et al 2014, Chen et al 2018,). The dissemination of AMR may occur by either of these routes, but often by a mix For a resistant strain to maintain a competitive advantage, the selection pressure must prevail otherwise the advantage will be lost. However, due to HGT the gene in which point mutation has occurred is able to spread rapidly from one micro-organism community to another. Both mechanisms are important, and both have different implications for the control of AMR (Allison et al 2015)

1.2.3 Population scale evolution of AMR

HGT is not only responsible for the dissemination of antimicrobial genes within a population, but also allows the purpose and role of these genes to evolve. As discussed in the section above, many microbes will develop resistance as a combined consequence of point mutation and acquisition of genes by HGT which confer resistance in the recipient micro-organism.

The host organism purpose of such conferring genes often includes (Allison et al 2015):

● Genes to detoxify the original host from the antimicrobial it produces as part of its defence mechanisms.

● Genes for specific enzymes that provide resistance to anti-bacterials such as penicillin. For example, beta-lactamase aids in counteracting beta-lactams which inhibit the biosynthesis of cell walls. .

● Genes responsible for multi-element efflux pumps that allow for the trafficking of signalling molecules from the micro-organism.

The process by which specific traits/features acquire functions for which they were not originally selected for is known as ‘exaptation’; this is one of the key drivers of evolution of antimicrobial resistance within and between populations of micro-organisms (Burnham et al 2017).

Once HGT has occurred; the original use of a feature acquired, such as the efflux pump, will not be relevant due to the different biochemical and genetic context, yet will still be expressed within the new host by the processes of exaptation. A good example of this is the acquisition of multielement efflux pumps (MEP). Due to microorganisms producing different signalling systems, the MEP will no longer be relevant (or appropriate) for the trafficking of signal molecules in and out of the cell in the new host. The MEP will however, still function in trafficking toxins and antimicrobials from the micro-organisms; therefore, functioning as antimicrobial resistance without inhibiting the processes within the new host (Martinez.J, 2012).