When normal bacteria are exposed to a drug, those that become resistant gain a huge and obvious advantage. Bacteria are notoriously quick to seize upon such evolutionary advantages and resistant strains rapidly outgrow the normal ones. Drug-resistant bacteria pose an enormous potential threat to public health and their numbers are increasing. MRSA for example, has become a bit of a media darling in Britain’s scare-mongering tabloids. More worryingly, researchers have recently discovered a strain of tuberculosis resistant to all the drugs used to treat the disease.
New antibiotics are difficult to develop and bacteria are quick to evolve, so there is a very real danger of losing the medical arms race against these ‘super-bugs’. Even combinations of drugs won’t do the trick, as resistant strains would still flourish at the expense of non-resistant ones. Antibiotic combos could even speed up the rise of super-bugs by providing a larger incentive for evolving resistance.
Clearly, fighting the rapidly evolving nature of bacteria is a dead end. So Remy Chait, Allison Craney and Roy Kishoni from Harvard Medical School used a different strategy – they changed the battle-ground so that non-resistant bacteria have the advantage. And they have done so using the seemingly daft strategy of using combinations of drugs that work poorly together, and even those that block each other’s effects.
The trio looked at two strains of the common bacteria Escherichia coli – one that was normal, and another that was resistant to doxycycline. Doxycycline is widely used to fight off a variety of bacterial invaders, but resistant E.coli use a specialised molecular pump to remove the drug. It can withstand 100 times more doxycycline than its normal counterparts.
First, the team hit the two strains with doxycycline and erythromycin, a combination of drugs that work particularly well together and enhance each other’s effects. The resistant strain was certainly more vulnerable to this double-whammy, but as expected, it always outperformed the normal bugs. With that advantage and enough time, it would inevitably evolve resistance to both drugs.
But Chait managed to remove this evolutionary impetus by combining doxycycline with a third drug, ciprofloxacin, a combination that would normally be useless. Doxycycline actually blocks the effects of ciprofloxacin, and the two drugs together are weaker than either alone. Predictably, the resistant bug did what it had evolved to do – it pumped out doxycycline. But in doing so, it also unwittingly removed the block on ciprofloxacin, restoring this second drug to its full killing power.
The normal strain encountered no such problem. By leaving the drugs alone, it never faced the full effects of either, and out-competed their more heavily-pummelled resistant cousins.
Chait cautions that it’s too early to transfer his findings across to hospital beds. The experiment used non-lethal antibiotic concentrations in a very controlled environment. But they have certainly pointed other researchers down a new and interesting path.
Combinations of drugs that block each other have previously been dismissed by doctors because they would require higher doses. But Chait’s study suggests that they could be the key to controlling bacterial drug resistance. We clearly can’t stop bacteria from evolving, but we can certainly steer the course of that evolution in our favour.
Reference: Chait, Craney & Kishony. 2007. Antibiotic interactions that select against resistance. Nature 446: 668-671.