From what we read, pharmaceutical research is rather stalled in this respect. New drugs coming onto the market are mainly minor tinkering with older approaches, and are both costly to develop and test but also have diminishing effectiveness. Yet entirely novel approaches seem hard to come by as well as prohibitively costly to develop.
Part of the apparent reason for the problem of increasing resistance is that to be economically viable, antibiotics tend to be broad-spectrum. That is, they work against whole classes of bacteria, which means that eventually they don't work against whole classes of bacteria. Developing an antibiotic directly against a specific bacterial type gets too costly for the potential payoff. At least that's the argument that's often made.
But might there be a wholly different approach? The BBC Radio 4 program Discovery on July 8 (here for download) took a refreshing and clever approach to this challenging subject. And it's based on a rather little-known characteristic of bacteria that has been part of their lives for about 3.5 billion years.
Bacteria are single-celled organisms that live and reproduce on their own (though sometimes a version of sexual reproduction is undertaken). Because of the way we've studied them in science, cell by cell, we have tended to think of them as lone wolves, but they are not. At least under some conditions, they live in large social groups (sometimes including members of more than one species). They form layered structures of large numbers of bacteria, called biofilms (or, in the fossil record, their mineralized remains are called stromatolites).
|Stromatolites in Shark Bay, Australia; Wikimedia|
A phenomenon associated with this environmental monitoring is called quorum sensing. Like all cells--and indeed all organisms including you and me--bacteria are constantly monitoring their environment. They secrete substances that they can also detect, and they can assess the concentration of these substances in their environment. This means they can sense how many of each other there are in the vicinity. This among other triggers is used to stimulate the formulation of a biofilm when there are enough bacteria in the vicinity to make that work.
|Five stages of biofilm development: (1) Initial attachment, (2) Irreversible attachment, (3) Maturation I, (4) Maturation II, and (5) Dispersion. Each stage of development in the diagram is paired with a photomicrograph of a developing P. aeruginosa biofilm. All photomicrographs are shown to same scale. Wikipedia|
Under some conditions, they respond to these signals by aggregating, huddling together and even forming physical connections among each other. Their gene expression pattern changes as well. Sometimes this is a protective means of herding in hostile environments. But other times, they aggregate because together they can mine a food source that an individual cell can't effectively access.
Unfortunately, sometimes that food source is you!
As the story was told on the BBC program, individual bacteria often are rather quiescent because too much activity could trigger an immune response and that means curtains to the bug. For example, if they were to attack your cells--and that, after all, is their menu!--the materials leaking from the cells would be detected by your immune system. But when there are enough bacteria, they decide to go ahead with their attack, and they activate mechanisms that lead to the lancing of your cells, releasing its cornucopia of nutrients. By then, there may be enough of them to overwhelm your immune reactions, and survive to live another day.
A stealth attack
The idea for a new approach is to design chemotherapeutic agents that interfere with the quorum sensing mechanism, not even trying to kill the bacteria but just preventing them from ganging up on you and eating away. If this works, and experimental trials are under way, then bacteria will face a very subtle attack: they won't 'know' that they're being targeted because all their cells and those of their fellow travelers' will be normal and unaffected. They just will never know that there are enough of them around to make a frontal assault possible.
The idea here is that resistance won't evolve because you're not putting the bacteria under any sort of stress. By contrast, antibiotics kill all vulnerable cells but that means that they open a clear path for any cells in which mutation has led to resistance to the agents. This makes evolution work against our epidemiological hopes, and (sorry, creationists) evolution works!
A limitation will be that different species of bacteria use different quorum sensing compounds or receptors and the like, so drugs may have to be more species-specific and less broad spectrum--and hence much more costly to develop. We'll see if this clever strategy works.
However, in the interview at least, the investigators seemed to be very naive about evolution, and as a result perhaps highly over-optimistic.
How evolution works and why it will again
Resistance to lethal attack is easy to understand. When a bacterial gene undergoes a mutation that, say, makes the cell no longer able to be bound by some chemical (an antibiotic), then the chemical will be harmless. Since mutations are always happening, and antibiotics work by molecule-to-molecule interactions, mutations leading to bacterial proteins that no longer bind to the antibiotic, and hence to resistance, are all too common.
This is one, rather classical, view of evolution. But there are others, and perhaps they are more subtle. After all there are differences among bacterial species in how they do their quorum sensing or what conditions trigger the formation of their biofilms. Since these vary among species, this must occur by mutational chance. Whether or not selection is involved, variants have become established.
Thus, even if you devise a way to confuse the current quorum sensing mechanism, without killing the bacteria, they won't be eating you (that's the idea), but will just continue to flit about singly and in rather a dormant state. But the food source (i.e., your cells) are still there as a waiting harvest. So it is inevitable that mutations in quorum sensing will lead some bacteria to be able to detect each other or to modify their predatory behavior. They will feast while their confused fellows die out.
This may take longer and be more complex an adaptive scenario, but it is hard to imagine that it would not occur. The BBC interviewees seemed unaware of this aspect of evolution, thinking that if you don't try to kill the bacteria you don't put adaptive selective pressure on them, but that is only one way that adaptation works. If there are other reasons to argue that bacteria can't adapt to interfering with their quorum sensing mechanisms, that wasn't stated.
Cooperation: a rigorous, vigorous, ubiquitous part of life
Our book, after which this blog was named, was written to take obsessive attention away from a competition-is-everything worldview that is so common in biology and biomedicine. Cooperation takes many forms and is far, far more widespread and ever-present than is competition (which, of course, does occur). The way bacteria join together to find a meal, and cause big problems, is an interesting example of cooperation even at the simplest level of life.