Air pollution and antibiotic resistance: is there cause for concern?

20th October 2023

Air pollution contains particulate matter that can carry antibiotic resistance genes, which have been found to accelerate microbial threats to human health. Here, Rod Tucker considers the extent to which air pollution could serve as a primary vector and driving force behind the increasing levels of global antibiotic resistance.

There‘s no doubt that global antibiotic resistance represents a major health challenge and is responsible for a huge number of deaths. For example, in a systematic review looking at the global burden of bacterial antimicrobial resistance in 2019, the authors estimated there were 4.95 million associated deaths.

In addition, data published in 2018 from the European Centre for Disease Prevention and Control estimated that around 33,000 people die each year in the in the European Union and European Economic Area as a direct consequence of infections with antibiotic-resistant bacteria.

Although antibiotic resistance represents the failure of a particular drug, there are a number of underlying factors responsible. Perhaps the greatest risk comes from interconnected human, animal and environmental habitats that are likely to contribute towards the emergence, evolution and spread of antibiotic resistance. In fact, resistance emerges as a result of the local confluence that occurs when bacteria colonise different human and animal hosts, enabling the spread of antibiotic resistant genes.

In response to the global rise in antibiotic resistance, countries have introduced antimicrobial stewardship programmes. Such initiatives represent a coordinated approach to promote the appropriate use of antimicrobials and reduce both microbial resistance and the spread of infections caused by multidrug-resistant organisms. 

Antimicrobial stewardship programmes are predicated on the notion that antibiotic use per se, is associated with the development of resistance. However, simply controlling usage may not be an effective means of reducing the rate at which resistance develops.

This was highlighted in a 2018 analysis of the factors driving global antimicrobial resistance. It found that reducing antibiotic consumption would be unlikely to control antimicrobial resistance because the spread of resistant strains and resistance genes seemed to be the most important contributory factor.

So, if this is case, what are the most likely vectors of resistant genes?

The role of air pollution

In 2018, Chinese researchers profiled the relative abundances of 30 antibiotic resistance genes (ARGs) in urban air carried in particulate matter. They found that urban air is being polluted by ARGs and different cities are challenged with varying health risks due to airborne ARG exposure.

Moreover, fine particulate matter, with a diameter of 2.5 μm or less (i.e. PM_2·5), is easily inhaled and therefore serves to increase the intake of airborne ARGs.

But to what extent is air pollution and the carriage of ARGs actually responsible for the spread of resistance?

A more recent study by Chinese researchers tried to answer this question. Writing in the journal Lancet Planetary Health, the team provided the first global estimates of antibiotic resistance and burden of premature deaths attributable to antibiotic resistance resulting from PM_2·5 pollution.

They used data from multiple sources and included a number of potential confounders, such as levels of air pollution, antibiotic use, sanitation services, climate, year, and region, from a total of 116 countries collected between 2000 and 2018.

Using raw antibiotic-resistance data on nine pathogens and 43 types of antibiotic agents, the team identified significant global correlations between PM_2·5 and antibiotic resistance (R²= 0.42 – 0.76, p<0.0001). Furthermore, these correlations appeared to strengthen over time.

The researchers also estimated that antibiotic resistance derived from PM_2·5 led to an estimated 0.48 million premature deaths and 18.2 million years of life lost in 2018 worldwide. In other words, with a positive and robust association between PM_2·5 and antibiotic resistance, the findings implied that globally, air pollution, and in particular PM_2·5, was an important driving factor.

Implications for practice

While the findings from the Lancet Planetary Health study are intriguing, this was an ecological study, which is more suited to the generation of hypotheses, and the finding of an association between air pollution and antibiotic resistance is not necessarily causal.

The authors of the paper also acknowledge some limitations. For instance, several low- and middle-income countries – the likes of which are most affected by antibiotic resistance – did not provide pathogen and antibiotic data.

In addition, the unrestricted use of antibiotics in animal farming was not examined in the study, which is a potentially important determinant of resistance in countries that also tend to have higher air pollution levels.

Finally, the authors also state that ‘some factors could be almost as important as PM_2·5 in contributing to antibiotic resistance’. This is another way of stating the obvious: there are lots of other possible factors that could account for the observed association. As information on such data was unavailable, it could not be included in the statistical models.

While it is possible that air pollution is a factor linked to increased levels of antibiotic resistance, in the absence of experimental evidence to support this premise, it remains yet another factor to be considered and addressed, if possible, in the global fight to reduce the adverse outcomes associated with increased antibiotic resistance.

Novel efflux pump inhibitor could help to combat antimicrobial resistance

25th July 2023

A novel membrane efflux pump inhibitor has been developed by a team of researchers at King’s College London, providing hope in the fight against antimicrobial resistance.

Bacteria can become resistant to antibiotics by drawing on their efflux pumps – proteins which allow them to regulate their internal environment by removing toxic substances. These reduce the concentration of antibiotics that reach the inside of the cell, increasing the likelihood of treatment failure.

King’s College London chemists have discovered how an efflux pump inhibitor can prevent this mechanism and therefore stop bacteria from becoming resistant to currently used antibiotics. This new method could prove cheaper and more efficient at dealing with antimicrobial resistance.

Efflux pump inhibitor mechanism

In 2017, researchers identified NSC 60339 as a periplasmic adaptor protein (AcrA) inhibitor with diverse functions, however the mechanism of AcrA inhibition was unclear.

In the current study, researchers used a combination of native and hydrogen/deuterium exchange mass spectrometry, molecular dynamics simulations and biophysical and cellular efflux assays to determine a mechanism of action for the AcrA inhibitor NSC 60339.

Their findings suggest that NSC 60339 becomes wedged between the lipoyl and αβ barrel domains, significantly restricting the structural dynamics of AcrA. They suspect that once locked in this position, AcrA cannot perform the necessary conformational transitions required during the functional rotation of the AcrAB-TolC pump used by bacteria to eject an antibiotic.

Ultimately, the work provides molecular insights into multi-drug adaptor protein function, which could be valuable for developing antimicrobial therapeutics.

Benjamin Russell Lewis from the Department of Chemistry at King’s College London said: ‘We discovered an inhibitor that acts as a ‘molecular wedge’ to neutralise the effective movement of the protein controlling the efflux pump response. Previous studies have identified that this particular inhibitor helped antibiotics kill bacteria but no one knew why or how, until now.

‘Traditional methods have focused on inhibitors targeting proteins in the inner cell membrane of bacteria. We demonstrate that inhibitors targeting the area between the inner and outer cell membranes could work better.‘

Dr Eamonn Reading, research fellow, Department of Chemistry at King’s College London, added: ‘Bacterial multidrug resistance continues to spread at alarming rates, threatening human health globally. If there ever is going to be a quick solution to dealing with something like a pandemic, employing efflux pump inhibitors will help us re-tool the existing treatments we already have.

‘We’ve helped lay the foundations with which future researchers and drug manufacturers can make more impactful alternative therapeutics to treat these devastating diseases without the need to make brand new antibiotics.‘

By providing the groundwork for how these cells and proteins interact at a molecular level, it is hoped that pharmacologists will be able to produce this new class of inhibitors and antibiotic treatments at speed and in time for the next generation of superbugs.