Would an anti-indole work?
Antibiotic resistance is one of the best examples of evolution in real-time and it’s also one of the most serious medical problems of our time. Emerging resistance in bacteria like MRSA threatens to bring on a wave of epidemics that may remind us of past, more unseemly times.
Given the threat that antibiotic resistance poses, it is paramount to understand the mechanisms behind this process. While considerable progress has been made in understanding the genetic basis of mutations that confer antibiotic resistance, much less is known about the population dynamics of bacteria that evolve this kind of resistance. Now, in the cover story of the latest issue of Nature, researchers from Boston University discover a novel and remarkable mechanism by which bacteria acquire resistance. The mechanism is effectively a form of bacterial altruism.
The researchers start by challenging successive generations of E. coli in a bioreactor with increasing concentrations of the antibiotic norfloxacin, which inhibits DNA synthesis by binding to DNA gyrase. Around the tenth generation or so, they notice something interesting. Not all bacteria have evolved resistance to the antibiotic, but there’s a very small population of bacteria with high resistance. However, in the next few generations, the other bacteria also seem to acquire this resistance. What’s going on?
It turns out that the small populations of bacteria which are highly resistant are actually ‘teaching’ their fellow bacteria to become resistant. They are doing this by a remarkably simple mechanism- by secreting the molecule indole into their environment. This indole acts as a signaling molecule that is mopped up by the other bacteria. The result is the activation of a variety of resistance mechanisms, including increased production of drug transporter proteins which are well-known to confer resistance by extruding drug molecules out.
Now indole is well-known as a component of signaling molecules. For instance, indole-3-acetic acid (IAA) plays many important signaling roles in plants and encourages cell growth and division. The detection of indole by itself was not surprising in this case, since all the bacteria secreted indole as part of their regular metabolism in the beginning. But what was surprising was the mechanism; as the antibiotic stressed out the bacteria, most of them essentially weakened and stopped indole-secretion with the exception of this small cadre of selfless individuals who kept on generating the molecular signal. Since production of indole in times of stress clearly requires an investment of energy, this was a bona fide case of bacterial altruism; sacrifice one’s own fitness to increase that of the group.
Ultimately though, we don’t want to just understand such novel mechanisms of antibiotic resistance but want to thwart them. Based on this mechanism I had an idea. If indole is so important for bacteria to acquire resistance, then one logical way to counter resistance would be to introduce an ‘anti-indole’ in their environment and mix it up with the natural molecule to cause confusion. This anti-indole would be a molecule resembling indole- an indole mimic and antagonist- that would effectively compete with indole for uptake, without causing any of the resulting effects.
Most likely this molecule would be a very close analog of indole, perhaps indole with a hydroxyl or fluoro group on it. Any small modification of indole would do, as long as it’s enough to confuse the bacteria. Of course we would also need to worry about bioavailability and toxicity, but I don’t see why the basic strategy would be completely unfeasible and why a proof-of-principle experiment could not be done in a petri dish.
Lee HH, Molla MN, Cantor CR, & Collins JJ (2010). Bacterial charity work leads to population-wide resistance. Nature, 467 (7311), 82-5 PMID: 20811456
I was *very* interested in this post, and I've just started to read about Indole and it's effects. I knew it had effects regarding the cell cycle, but i hadn't heard of it being involved in antibiotic resistance! I suppose one of the first tests to do with this would be to see if the indole-knockout bacteria were any more or less resistant to antibiotics, and it would be *very* interesting if they were.
ReplyDeleteThere are a few Brassica indole derivatives that have had some studies done for other reasons, perhaps they might have anti-indole properties.
ReplyDelete@Lab Rat: Good idea. Knockoouts would provide some pretty useful information.
ReplyDelete@Pat: That's exactly what I started thinking about, especially indole-3-carbinol.
Nice post Ashutosh. I wonder how does the altruism come in picture. Is there some way by which some bacteria understand that the rest of the population is dying and thus keep excreting the indole? It cannot be just a decrease in the indole signal. If it is that then does it mean that every bacterial group has a few strong members who are able to detect a loss in indole signals and thus realise the importance of keeping the excretion of indole going?
ReplyDeleteThis research raises a lot of questions...interesting. :)
Great question Akshat! Maybe the indole-prooducing bacteria also get some benefits by way of feedback. Or maybe it's just a case of accidental benefit; a mutation in the small group of indole-producing bacteria happens to help the others. Such scenarios are not unknown in evolution.
ReplyDeleteCould indole produced and accumulated before challenging the population with antibiotics affect the basal resistance of the population at a whole? If so,that might also affect development of resistance and survival of sensitive bacteria. I would guess such an effect of indole produced before challenging the cells would depend a lot on population sizes and whether bacteria are transferred to a fresh medium when challenged, of if antibiotic is just being added to the medium they have started growing in...
ReplyDelete