Metabolised antibiotics can drive antimicrobial resistance just as much as their parent compounds

Metabolites of antibiotic drugs have been shown to drive antibiotic resistance in bacteria, in some cases to the same degree as the antibiotic itself. The finding has researchers rethinking how antibiotics and their metabolites behave in our waterways.

Antibiotic, or antimicrobial, resistance (AMR) is one of the top public health issues globally, linked to more than 1 million deaths in 2021 alone. It occurs when bacterial communities mutate to develop defences against the antibiotics designed to eliminate them. And while it is well known that drugs present in our waterways can drive AMR in bacteria, less is known about their transformation products – the chemicals antibiotics generate when they break down in our bodies and in the environment.

To investigate this, a team led by Pooja Lakhey from the University of Queensland in Australia collected samples from a wastewater treatment plant in Brisbane and another in Falmouth, UK. They exposed these samples to three different classes of antibiotics and their transformation products in the lab and analysed how strongly resistant the bacteria in each sample became.

The drugs that they tested included fluoroquinolones and the MLS group (macrolides–lincosamides–streptogramins), which are both used widely in humans, and the sulfonamides, an antibiotic used primarily in agriculture and veterinary applications.

In total, 15 different transformation products were tested across these three classes. In every transformation product tested, the team found some level of potential for AMR.

According to Lakhey, it was a surprising result. ‘Most of the time we consider metabolites to be not harmful, or less harmful, than the parent compounds,’ she says. ‘But what if they’re not as harmless as we thought they would be?’

Once antibiotics enter our waterways, they are very difficult to remove. While wastewater treatment plants can capture and degrade some pharmaceuticals, they are not designed for this specific purpose. ‘These plants are geared towards lots of other things and if they remove some antibiotics, then that’s a bonus, but that’s certainly not an aim,’ says Lena Ciric, an expert on microbiology in built environments from University College London, UK.

Studies such as these highlight another layer of complexity, suggesting that simply monitoring the parent antibiotic may not give us the whole picture. ‘[This work] reinforces the idea that we’re likely underestimating environmental AMR selection pressures,’ comments Holly Tipper, a molecular microbiologist at the UK Centre for Ecology and Hydrology. ‘It points to a clear need for more research, which I think should include the development of community-level assays to better capture biological effects.’

Lakhey hopes that the finding encourages a reframing of risk assessments for environmental contaminants to include transformation products.

For Ciric, this is another piece in the puzzle of fighting antibiotic resistance. ‘AMR is a worry, and the presence of antibiotics and their metabolites in our water systems is a contributing factor,’ she says. ‘But there are lots of contributing factors, and this is just one of them. Trying to address AMR requires us to be acting on lots of different fronts.’