Study Identifies Mechanisms Underpinning Rapid Antibiotic Resistance
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A new study has found that some bacteria can rapidly develop resistance to antibiotics by modifying pumps that remove drugs from the inside of bacterial cells. The research is published in Antimicrobials and Resistance.
The threat of drug-resistant pathogens
Antimicrobial resistance occurs when microorganisms, such as bacteria and fungi, develop mechanisms that protect them against the drugs designed to kill them. The rise of antibiotic-resistant bacteria threatens the future use of these drugs against infections, which could have potentially deadly consequences – the World Health Organization has declared antimicrobial resistance as a top 10 global public health threat.
Superbugs have several different ways that they can develop resistance: inactivating or avoiding antibiotic drugs, preventing antibiotics from entering their cells or removing them before they take effect. However, exactly how they achieve this is still being investigated by scientists.
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In the current study, researchers from the University of East Anglia’s (UEA) Norwich Medical School and the Quadram Institute investigated how Salmonella bacteria developed resistance after exposure to two different antibiotics.
“This work simulates what happens in the real world where bacteria are constantly exposed to varying concentrations of antimicrobials,” said Dr. Eleftheria Trampari, first author of the study and Quadram Institute researcher. “Studying how resistant strains emerge and predict which drugs they will not respond to can be helpful in developing diagnostics and treatment strategies.”
Discovering resistance mechanisms
Bacteria were grown in two different states that mimic how they live in the environment – either planktonic (floating in a liquid growth medium) or as a biofilm (clustered together and attached to a surface within a self-produced matrix). Most bacteria exist as biofilms, which provide protection against environmental stresses.
The cultured bacteria were exposed to two antibiotics – cefotaxime and azithromycin – that created a selection pressure, simulating evolution and a “survival of the fittest” scenario. This positively selects the bacteria best adapted to survive in the presence of antibiotics.
The resulting resistant bacteria underwent genome sequencing to discover which genes differed in the resistant bacteria compared to the original sensitive bacteria.
The researchers found that resistance to both of the antibiotics tested led to different mutations in a molecular pump, AcrB, used by Salmonella to flush out toxic compounds from within the cell.
In collaboration with researchers from the University of Essex and the University of Cagliari, the team investigated how these mutations changed the function of this pump, discovering that they affected it in different ways. One mutation made it easier for the drug to pass through the pump, while the other increased the ability of the pump to recognize the drug which boosted its efficiency.
Furthermore, when researchers scoured databases containing the genomes of Salmonella isolates sampled from the outside world, they found that one of these mutations had already occurred several times since 2003. They found evidence of the mutation in isolates from patients, livestock and food across the UK, US and European Union.
Together, the results of this study propose that these pumps have a major role in Salmonella’s defense against antimicrobials, and it is hoped that these results may improve how antibiotics are used to help limit the spread of antimicrobial resistance.
Mark Webber, honorary professor at Norwich Medical School and senior author of the study, explained: “Knowing the details of the mechanisms bacteria develop to become resistant is a key step to understanding antimicrobial resistance. We hope that this kind of work to understand when and how resistance emerges can help us use antibiotics better to minimize selection of resistance.”
Reference: Trampari E, Prischi F, Vargiu AV, Abi-Assaf J, Bavro VN, Webber MA. Functionally distinct mutations within AcrB underpin antibiotic resistance in different lifestyles. npj Antimicrob Resist. 2023;1(1):1-13. doi: 10.1038/s44259-023-00001-8
This article is a rework of a press release issued by the University of East Anglia. Material has been edited for length and content.