We all know and quail at the thought of superbug gonorrhea, let alone cholera. Almost half a million people a year catch multi-drug resistant tuberculosis, says the World Health Organization. Even the bacteria involved in common acne can turn deadly and untreatable. Now scientists at the Hebrew University of Jerusalem have gained crucial insight into the way superbugs evolve, which could lead to the development of new drugs.
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Three years ago the Jerusalem team showed that some bacteria can survive antibiotic treatments if they are dormant for the duration of antibiotic treatment. If however the antibiotic is still there around when they wake up, they die – unless they also develop resistance to the drug.
When a bacterium is inundated with antibiotics and survives thanks to a random mutation that happens to cause a transient dormancy mechanism, that is called tolerance. When a bacterium mutates to live happily ever after in a sea of the drug, that is called resistance.
And now the scientists at Hebrew University have some really bad news, reported today in Science after developing the one mutation, the dormancy mechanism, bacteria can evolve resistance 20 times faster than normal.
Stopping their parade
It helps to know that some antibiotics eradicate bacteria by preventing them from reproducing.
This mechanism was detected by Prof. Nathalie Balaban and Irit Levin-Reisman, who exposed the germs to a daily dose of antibiotics until resistance was established.
A lethal dosage of the drug would kill most of the bacteria in the petri dish, but not all. Some would survive by entering into temporary dormancy, during which time they do not reproduce. Their "sleep" protected them from antibiotics that target proliferating bacteria.
The experiments were done on intestinal bacteria, Escherichia coli – two innocuous lab strains and one pathological strain isolated from a patient. The results of the research only apply to E. Coli, but, Balaban points out, tolerance has been demonstrated in almost all kinds of bacteria, and even in yeast. It is true that in theory the experiment would have to be repeated per species, but she feels confident that the principle would remain the same.
What the team found is that once E. Coli mutated to be tolerant (sleep when the drug is around), they could rapidly acquire mutations to resistance.
Why? The explanation is mathematical, Prof. Balaban told Haaretz. "It isn't that something in the bacteria that morphs into a superbug is particularly different," she says.
Tolerance is achieved quite easily, because a lot of mutations can lead to it, Balaban explains. Mutations develop and disappear in populations. But the coupling of the tolerance and resistance mutations greatly increases the survivability of the resistance mutation.
It is though the first mutation, sending the dears to sleep, acted as a stepping stone for the next mutation that conferred resistance. Or, as they say sorrowfully in hospital wards, that created the superbug.
The solution for this particular conundrum would seem to be to develop antibiotics that work on dormant bacteria as well. Balaban points out that dormancy can arise sprontaneously or may be caused by antibiotics. Killing them too would be useful. Otherwise at some point the antibiotic will be gone, they will wake up and proliferate.
"There aren't many antibiotics that can do that, and the ones that exist often have severe side effects. So they aren't used without a good reason," says Balaban. Hence the need to develop new ones that preferably have fewer and less onerous side effects.