Drug resistant bacteria are, justifiably, a serious cause for concern. Most of the attention has focused on mutations or genes that confer resistance to our current repertoire of antibiotics. But bacteria have a second way to avoid being offed by our drugs: a tiny fraction of many bacterial species will go into a sort of suspended animation. Then, after the treatment is over, a few of these cells will pop back out, setting up the risk of a persistent, recurring infection.

So, the challenge has been figuring out how to kill off these dormant cells, since most of our antibiotics target cells that are rapidly growing. Now, researchers have found a molecule that induces dormant cells to kill themselves by indiscriminately digesting their own proteins. And, although bacteria can easily evolve resistance to this new antibiotic, doing so leaves them vulnerable to traditional ones.

We've been aware of bacterial dormancy since the 1940s, but its relevance to persistent infections wasn't obvious at the time it was discovered. Many species, including the familiar E. coli, have the ability to largely shut down their metabolism and grow at an extremely slow pace. These persisters occur spontaneously in growing cultures, at rates as low as one-in-a-million bacteria. They remain genetically identical to their fast-growing peers; it's just that a random process triggers a different program of gene regulation, altering the cells' behavior.

Persisters pose a problem because they typically don't respond to traditional antibiotics. These antibiotics typically do things like destabilize the cell wall so that it fails during cell division, or they cause the production of malformed proteins. If the cell's not dividing much or at all, it has time to repair much of this damage before it causes too many problems. As a result, even as an antibiotic may be laying waste to the rapidly growing cells that are causing an infection, a few persisters get left behind, ready to restart the infection at some random point in the future.

This led some researchers to consider the possibility of developing an antibiotic that essentially causes a bacterium to kill itself. Fortunately, microorganisms have been engaging in chemical weapons arms races for countless generations, and one bacteria species had already evolved a chemical to do just that. Streptomyces hawaiensi comes from the same genus of bacteria that has given us tetracycline and erythromycin; this particular species makes antibiotics called acyldepsipeptides, or ADEPs. And ADEPs have a very particular method of attacking bacterial cells.

All cells tend to have problems with malformed proteins; these are either made improperly or pick up some form of damage. If left around, these proteins can start causing problems within the cell, since they'll get in the way of the healthy proteins that are just trying to do their jobs. As a result, cells have ways of getting rid of them, typically a complex called a protease that chews them up into individual amino acids that can then be used to make new proteins. To make sure that the cell doesn't digest healthy proteins, this protease is carefully regulated.

In bacteria, the protease takes the form of a barrel open at both ends. Normally, the pore down the middle is squeezed too tight for a protein to fit in. But, when a damaged protein is detected, a second protein binds to the protease, opening the pore and allowing it to get to work.

The ADEPs bind to this protease and cause the central pore to open up, even when there are no misfolded proteins around. And, when opened in this manner, the protease gets very indiscriminate in what it digests. The researchers behind the new paper found that, of the 1,700 or so proteins made by a healthy bacterium, over 400 were digested in the presence of ADEPs. And, more importantly, this digestion took place both in rapidly dividing cells and in dormant persisters. The researchers showed that ADEPs could completely wipe out bacterial infections so that there's nothing left.

Or, at least this worked most of the time. As in so many cases, bacteria could evolve resistance. It turns out that cells could survive without the protease, and any mutation that disabled the gene that encodes it would allow the cells to survive.

This would seem to be a dead-end for this promising avenue of research, except for one thing: the bacteria that resisted the ADEPs were susceptible to normal antibiotics. Combinations of ADEP and several other drugs could wipe out persistent staph infections, including those deep-seated in muscles.

The authors don't seem to understand why this is the case (or, if they know, they're not saying). There are several reasons why this might happen; the protease could be necessary to maintain the persister state or to deal with the stress response normally triggered by antibiotics. But the key fact is that it works; ADEPs turned existing antibiotics that can't clear persistent bacteria into effective treatments, even though it's relatively trivial to evolve resistance to them.

More generally, the researchers behind the paper suggest that the general approach represented by ADEPs may be a promising route to the development of new antibiotics. We've mostly been focused on finding ways to keep bacteria from growing by blocking something. It's possible that there are many other ways to activate something in a way that's lethal to the cell.

Nature, 2013. DOI: 10.1038/nature12790 (About DOIs).