How bacteria develop resistance to antibiotics

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Antimicrobial resistance is a growing problem of global importance. The rise of resistant “superbugs” threatens our ability to use antimicrobials such as antibiotics to treat and prevent the spread of infections caused by microorganisms.

The findings are expected to improve the way antibiotics are used to help prevent the further spread of antimicrobial resistance.

Professor Mark Webber from UEA Norwich Medical School and the Quadram Institute said: “Understanding the details of the mechanisms that bacteria develop to become resistant is a key step in understanding antimicrobial resistance. We hope such work allows us to understand when and how resistance arises. may help us to better use antibiotics to minimize the selection for resistance.”

The team studied how exposure to antimicrobials leads to the emergence of resistance.

Generally speaking, superbug defenses against antibiotics involve inactivating or evading drugs, preventing them from entering their cells, or removing them from their cells before they can have any effect. But exactly how they do this is still being worked out.

In this new study, QI’s Dr. Eleftheria Trampari, Prof. Webber and colleagues recreated the evolutionary stress that leads to antimicrobial resistance by exposing Salmonella bacteria to two different antibiotics.

The bacteria were allowed to grow and reproduce in two different states that mimic how they live in the environment.

Some were planktonic, floating in a liquid broth, but others were in biofilms. Bacteria form biofilms on surfaces, as a way of protecting themselves against stress, and most bacteria in the real world exist in a biofilm.

Hundreds of generations of bacteria were cultured and exposed to antibiotics, and in this simulation of evolution, survival of the fittest selected those bacteria best adapted to cope with the presence of antibiotics.

To identify how these ‘winners’ had become resistant, the researchers sequenced the genomes of the resistant bacteria, to identify which genes had changed compared to their non-resistant ancestors.

They found that both antibiotics selected for different mutations in a molecular pump that Salmonella uses to rid itself of toxic compounds inside its cells. With colleagues from the University of Essex and the University of Cagliari, they found that these two different changes altered how the pump worked in entirely different ways. One made it easier for the bombs to trap the drugs, the other made it easier for the drugs to slip through the bomb.

A search of databases of genomes of Salmonella isolates found that one of these mutations has also arisen several times in the real world, in Salmonella from patients, livestock and food in the UK, US and EU, since 2003.

The results confirm a leading role for these pumps as the first line of defense against antimicrobials.

“This work simulates what happens in the real world, where bacteria are constantly exposed to varying concentrations of antimicrobials,” said Dr. Eleftheria Trampari of the Quadram Institute and first author of the study. “Studying how resistant strains emerge and predicting which drugs they won’t respond to may be helpful in developing diagnostic and treatment strategies.”

The study was supported by the Biotechnology and Biological Sciences Research Council, part of UKRI.