The resistance shuffle

Bacteria carry antibiotic resistance genes on movable sections of DNA, allowing the organisms to shuffle their genetic code to resist antibiotics.
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Microscope image of two fluorescent strains of P. aeruginosa. Image credit: Sean Booth (CC BY 4.0)

From urinary tract infections to bacterial pneumonia, many diseases can now be treated through a course of antibiotics. Yet bacteria have evolved to respond to this threat, gaining new antibiotic resistance genes that allow them to evade the drugs. Addressing this growing issue requires to either discover new antibiotics, or to stop resistance before it emerges – a strategy that can only work if scientists know exactly how this mechanism takes place.

For bacteria, it is a waste of resources to produce the proteins that confer resistance if antibiotics are absent. In fact, doing so can decrease their chance to survive and reproduce. A genetic element known as an integron can help to manage that burden. This piece of genetic information is formed of a succession of ‘cassettes’ containing antibiotic resistance genes. More proteins are made from the genes present at the start of the integron, compared to the ones towards the end. When bacteria encounter antibiotics, an enzyme called integrase is activated, allowing the organisms to shuffle the order of their cassettes in the integron. It is thought – but not yet proven – that this mechanism helps bacteria to activate their resistance ‘on demand’.

To find out, Souque et al. engineered the bacteria Pseudomonas aeruginosa to carry a custom integron with three cassettes, each helping the organism to resist to a different antibiotic. In addition, only half of the bacteria had a working integrase and could therefore shuffle their gene cassettes. The organisms were then exposed to an increasing amount of the antibiotics for which the cassette in the last position provided resistance. The bacteria with a working integrase survived longer than those without, as they were able to shuffle their cassettes and move the useful antibiotic resistance gene into top position. In addition, the cassettes carrying the genes to resist to other types of antibiotics were excised from the genetic information and lost.

Understanding integrons could guide future antibiotic treatment strategies, for instance by combining antibiotics with chemicals that block integrase activity. It might also be possible to force bacteria to delete resistance cassettes by cycling through different antibiotics.