Drug-resistant mutants produce a molecule that boosts drug tolerance in the susceptible ones

The long-held notion on how bacteria develop resistance to antibiotics stands challenged.

The conventional thinking is that continuous exposure to antibiotics or exposure at sub-optimal levels can facilitate some bacteria to develop mutations that render them resistant to a particular antibiotic. And this antibiotic-resistant mutation is then passed on to succeeding generations, and in time the antibiotic-resistant bacterial population becomes dominant.

But a paper published today in Nature reveals how drug-resistant mutants resort to a quicker way to make the overall population of bacteria resistant to a particular antibiotic in the very same generation.

Helping hand

The antibiotic-resistant mutants lend a helping hand to protect other drug-susceptible species, the study shows. This is the first time a study has shown that drug-resistant mutants need not become the dominant species to become a threat. Surprisingly, the mutants protect the entire population even though it is at some cost to themselves.

The study also highlights the danger of using antibiotics at sub-optimal levels.

A study done in a bioreactor used the drug, Norfloxacin, at lower concentrations than was actually required to kill Escherichia coli bacteria. In fact, the dosage of the drug was chosen such that only 60 per cent of growth was inhibited.

Still survived

The concentration of the drug was increased every day. Surprisingly, despite increasing the dosage on a daily basis, even the bacteria that had not developed the drug-resistant mutation, and therefore had low-resistance to the drug, still managed to survive.

Even on day nine, the bacteria with low-resistance survived despite the fact that the drug concentration was much higher than what was required to kill the bacteria. The researchers note that a vast majority of individual E. coli were “less resistant to the drug than the population as a whole.”

They also found that the norfloxacin-resistant mutants increased in number first, followed by an overall increase in the population of low-resistance E. coli.

So how was this achieved? “A few highly resistant mutants improve the survival of the population's less resistant constituents,” the researchers note. And this was through the production of a small signalling molecule called indole that improves stress tolerance (in this case, the ability to survive the drug) in E. coli.

“We propose that indole produced by the drug-resistant mutants was protecting its less-resistant neighbours,” the authors write.

Role of indole proved

To further ascertain the role of indole, the researchers added the molecule and found those E. coli, which had low-resistance to the drug, increased and survived at drug concentrations that were many times more lethal.

The results were the same when the experiment was repeated using a different drug — gentamicin.

This shows that the mechanism by which the drug-resistant mutants protect the rest of the population is the same, immaterial of the drug in question.