Non-antibiotic drugs promote antibiotic resistance

THE widespread use of antibiotics encourages the pathogens they are directed against to become inured to their effects. That is well known. But antibiotics cause damage to non-target species as well, so these, too, tend to evolve immunity. Since most antibiotics are administered by mouth, the many bacteria that live peacefully in the human gut are particularly susceptible to such evolutionary pressures.

The medical consequences of this are ill-understood, in part because most gut bacteria are anaerobes (meaning they flourish only in the absence of oxygen) and so are difficult to culture. But Lisa Maier of the European Molecular Biology Laboratory, in Heidelberg, and her colleagues have, nevertheless, grown 40 of the most common strains of them in anaerobic conditions. They have then gone on to expose those cultures to hundreds of drugs for a range of ailments, at the sorts of concentrations that might be encountered in the human intestine. Their study, published this week in Nature, has revealed an unexpected avenue by which gut bacteria can become resistant to antibiotics: exposure to drugs that were designed to act on human cells rather than microbial ones.

Of the drugs in the study, 156 were antibacterials (144 antibiotics and 12 antiseptics). But a further 835, such as painkillers and blood-pressure pills, were not intended to harm bacteria. Yet almost a quarter (203) did. These accidental bactericides included proton-pump inhibitors such as omeprazole (used to treat acid reflux), calcium-channel blockers (to lower blood pressure), antihistamines, painkillers and antipsychotics. (In the case of antipsychotics, these chemically diverse drugs seemed to affect many of the same strains of gut bacteria. That suggests their effects on the brain could, in part, be a result of their influence on gut flora).

The researchers noticed too that the strains of bacteria most resistant to the effects of drugs not aimed at them were also those most resistant to antibiotics. This observation implied that these bacteria were using similar means to defend themselves against both sorts of medicine.

To check if that was indeed the case, Dr Maier and her colleagues first looked at a particular strain of a common gut bacterium, Escherichia coli, which they knew carried an antibiotic-resistance gene called tolC. Bacteria that possess tolC can make a protein which works as an antibiotic-expulsion pump. The researchers found that E. coli carrying tolC were resistant to the effects of both antibiotic and non-antibiotic drugs, and that E. coli engineered to lack it became susceptible to both.

The team then conducted a foray through the genome of E. coli, intended to look at the protective effects of pretty well every gene the bug possesses. To this end they bought a library of 4,000 strains of E. coli, each of which was engineered to overproduce the protein encoded in one particular gene, different for each strain. They studied the effects of seven non-antibiotic drugs on each of these strains.

They found many cases where proteins (and thus genes) which protected bacteria from these seven drugs were ones already known to make them resistant to antibiotics. In sum, their work suggests that bacteria often use similar mechanisms to evade all classes of drug. These can be spread by the bacterial habit of trading DNA not only with conspecifics but also with other members of the bacterial domain. This means the gut bacteria of patients consuming (say) painkillers or proton-pump inhibitors might evolve a resistance that they then passed on to a pathogen that subsequently infected the body.

That is worrisome. Drug-resistant infections could, by some estimates, become responsible for 10m deaths a year by 2050, up from 700,000 today. However, Dr Maier’s study also brings some good news for the fight against antimicrobial resistance. Some strains she looked at which were resistant to antibiotics nevertheless succumbed to one or more of the non-antibiotic drugs thrown at them. This could be a starting point for the development of new antimicrobial agents which would eliminate bacteria that have proved intractable to other means. Given that all the drugs tested have already been approved for human use, albeit for unrelated conditions, this is a path well worth exploring.