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Selection for antimicrobial resistance in a complex community context

Periodic Reporting for period 1 - SARCOM (Selection for antimicrobial resistance in a complex community context)

Reporting period: 2017-12-01 to 2019-11-30

A predicted 10 million human deaths per year by 2050 can be attributed to bacteria that evolved the ability to withstand antibiotics. With the increase in antimicrobial resistance (AMR) in a wide range of pathogens traditional antibiotic treatment is losing effectiveness. AMR is now recognized by the WHO as one of the major human health threats our society is facing, and thus combatting AMR is a key strategic priority for EU-wide research funding. To successfully mitigate the spread of AMR it is thus crucial to understand under which conditions, here mainly which concentrations of antibiotics, AMR is positively selected for by giving the bacterial host a growth advantage.

The majority of experimental work trying to identify these conditions has looked at selection in single species and hence not explicitly considered a crucial feature of the lifestyle of bacteria: microbes are typically embedded within complex communities of many interacting, diverse bacterial species. This is always the case within human and animal microbiomes, in which antibiotics are most likely applied. Consequently it remains difficult to assess risks in real world scenarios by exclusively using results from single strain laboratory experiments that do not consider bacterial interactions.

During this fellowship my aim was to overcome this problem by investigating how being embedded in a complex, natural microbial community of many bacterial species changes the spread of and selection for AMR in comparison to single strain lab experiments.

I was finally able to conclude that selection for antimicrobial resistance is indeed reduced when other community members are present, since these community members can interact with both the resistant as well as the susceptible strain.
In addition I showed that not only antibiotics, but also other factors, such as the ubiquitous environmental contaminants, heavy metals and microplastics, contribute to the spread of AMR in bacterial communities.
Studies to date concluded that antibiotics at extremely low concentrations can select for resistance mechanisms in single strain experiments. However, these tests barely mimic natural environments where bacteria are embedded within complex communities consisting of thousands of bacterial species. During my fellowship I overcame this limitation and showed that competing with other community members increases an antibiotic’s minimal selective concentration for antibiotic resistance in a bacterial species by more than an order of magnitude. To gain insights into the mechanisms underlying this phenomenon I used mathematical modelling and community wide DNA sequencing analysis to determine resistance gene profiles of the microbial communities. Using these complementary methods, I was able to finally identify two major mechanisms that cause the reduction in selection for antibiotic resistance when embedded in a complex community: First, resistance is more costly to its bacterial host while competing with other community members, and second, other community providing protection to the susceptible strain to withstand the antibiotic pressure more efficiently.

In addition other bacteria in the community can contribute to the spread of AMR by engaging in horizontal gene transfer or “bacterial sex”. Since bacteria propagate asexually, they evolved the ability to exchange genes and hence genetic traits like antimicrobial resistance with each other. During this fellowship I established that bacteria that have been previously exposed to metals are more likely to take up mobile antibiotic resistance genes from their neighbours. Simultaneously, bacteria in freshwater that are living on microplastics are far more likely to gain antibiotic resistance traits through horizontal gene transfer than their planktonic, free-living counterparts. I finally developed a method to visualize, how bacteria can not only accept mobile AMR genes from other bacteria in the community they are living in, but actively mobilize them from their neighbours.

This and other work during this fellowship has led to a total of 8 published or submitted manuscripts so far, with 5 more manuscripts in preparation. I have further presented my research at 4 international conferences, 1 workshop, 1 symposium and was invited to give a research seminar in Australia.

No website has been developed for the project.
My results stress that, when assessing the risk of antibiotic concentrations for selection of resistance genes as well as their potentially pathogenic hosts, it is crucial to take environmental considerations, like complex community context, into account. Previous laboratory experiments suggested that antibiotics at extremely low environmental concentrations can select for resistance mechanisms in single strains. My research shows that selection under environmentally relevant conditions, with a diverse bacterial community present, happens more likely at higher concentrations than previously assumed. This further highlights that maintaining a healthy microbiome within the patient decreases the likelihood of positive selection for pathogens that might have acquired resistance and should hence be of high priority.

In addition I showed that not only antibiotics, but also other factors, such as the ubiquitous environmental contaminants, heavy metals and microplastics, contribute to increased horizontal transfer of AMR, and need to be recognized by policy makers as potential causes of elevated levels of AMR.

During this fellowship I contributed to our understanding of under which conditions AMR is positively selected for and transfered. This is ultimately crucial to develop mitigation strategies and overcome the current AMR crisis.
Graphic: Selection for resistant superbugs is reduced when embedded in a complex community