Research shows alternating antibiotics could make resistant bacteria beatable

Researchers from the University of Exeter has shown that the use of ‘sequential treatments’ – using alternating doses of antibiotics – might offer effective treatment against bacterial infection.

Crucially, the research also demonstrates this technique for administering treatment also reduces the risk of the bacteria becoming resistant to antibiotics, and so maintaining the long-term effectiveness of the drugs.

The collaborative international research, led by Professor Robert Beardmore from the University of Exeter and funded by EPSRC, is published in leading scientific journal PLOS Biology.

The research indicates that drug treatments with two antibiotics can be designed to kill bacteria at dosages that would ordinarily cause rapid development of drug resistance and sustained bacterial growth, when administered alone or in combination.

The researchers used a test-tube model of a bacterial infection to show that, even in bacteria that already harbour drug resistance genes, sequential treatments could deal with the bacteria, even when much higher doses of single drugs or mixtures of two drugs failed to do so.

“Our study finds a complex relationship between dose, bacterial population densities and drug resistance,” said lead author, Professor Beardmore. “As we demonstrate, it is possible to reduce bacterial load to zero at dosages that are usually said to be sub lethal and, therefore, are assumed to select for increased drug resistance.”

The researchers also discovered that, although sequential treatments didn’t suppress the rise of all drug resistance mutations in the bacteria, one drug would ‘sensitize’ the bacteria to the second drug, and therefore reduce the risk of resistance occurring.

Study co-author Dr Ayari Fuentes-Hernandez said: “Research has concentrated for decades on synergistic drug cocktails. We believe ‘sequential synergies’ might be just as potent if we look for them, this research will therefore be of interest to the pharma and dwindling antibiotic discovery communities.”

While bacteria are masters at adapting to antibiotic challenge, this research suggests that there is a way to use this adaptation against them. The fluctuating environments created by well-designed sequential treatments can sensitize bacteria and render them susceptible to concentrations of antibiotics that would normally induce drug resistance and continued existence.

EPSRC-funded researcher, Dr Jessica Plucain, said that although extensive further work is now needed to will be needed before sequential treatments make it in to the clinic, the research demonstrates that they can be effective even when using drug doses below their maximal potency.

She said: “One outcome of this highly surprising result will be to set in motion a series of studies to determine ways of using antibiotics not only in combination, but sequentially and with the potential for lower dosages than is currently thought possible.”