Antimicrobial resistance occurs when pathogens such as bacteria develop the ability to resist the drugs designed to kill them. Now, UK researchers have uncovered the mechanism underpinning antibiotic resistance and hope the knowledge might be exploited to develop new drug therapies.
The misuse and overuse of antibiotics have contributed to the development of drug-resistant bacteria. Antibiotic resistance is a serious public health problem, increasing the likelihood that bacteria will spread from person to person more easily.
Gut bacteria possess thin filament-like appendages called F-pili that allow them to connect to one another and transfer packets of antimicrobial resistance (AMR) genes, a process called conjugation. It was initially thought that the gut’s harsh conditions – acidity, heat, and turbulence – negatively affected F-pili, making gene transfer more difficult. However, researchers from Imperial College London have discovered that the opposite is true: F-pili, and their ability to transfer AMR genes, are unaffected by conditions in the gut and strengthened by their molecular structure.
“The death toll from antimicrobial resistance is expected to match cancer by 2050, meaning we urgently need new strategies to combat this trend,” said Jonasz Patkowski, lead author of the study. “Much of the spread of resistance is driven by bacteria swapping genes, so a detailed understanding of this process could lead to new ways to interrupt it.
The researchers tested the existing hypothesis, which states that F-pili are fragile when agitated, by conducting a simple experiment: they shook samples of Escherichia coli (E. coli), a bacterium commonly found in the large intestine, while the F-pili conjugated. They found that agitation actually increased the efficiency of gene transfer between bacteria. Importantly, they found that the shaken bacteria clumped together to form a biofilm, a kind of ‘fence’ that protected inner bacteria from surrounding antibiotic molecules.
Keen to test the F-pili’s resilience, researchers used ‘molecular tweezers’ to pull on the end of the structure, which was found to be highly elastic and sprang back without breaking. The F-pili also survived the application of sodium hydroxide (caustic soda), urea, and temperatures of 212 °F (100 °C).
It’s already known that F-pili are made of subunits of interlinked phospholipid molecules, but the researchers wanted a better understanding of their molecular composition. Creating F-pili without phospholipids, the researchers repeated the pull test. The phospholipid-free F-pili disintegrated easily, demonstrating how important these subunits are to the structure’s strength and elasticity.
The study highlights how F-pili have adapted to spread AMR genes more efficiently and effectively and goes a long way towards improving our understanding of antibiotic resistance and how the process might be interrupted.
“Making F-pili is very costly to the bacteria in terms of resources and energy, so it’s no surprise they are worth the effort,” said Tiago Costa, corresponding author of the study. “We have shown how F-pili accelerate the speed of antibiotic resistance and biofilm formation in turbulent environments, but the challenge now is to find ways to combat this very efficient process.”
The researchers believe that now that they better understand F-pili’s strengths and weaknesses, the structures could be used to develop new drug delivery systems.
“It’s hard to find a tubular appendage with such strong properties,” Patkowski said. “Bacteria use it to transfer genes, but if we could mimic these properties, we could use similar structures to precisely deliver drugs where they are needed in the body.”
The study was published in the journal Nature Communications.
Source: Imperial College London
