The Newest Catch-22 of Antibacterial Drug Resistance

If one really wanted to help out a harmful bacterium in its quest to evade antibiotic drugs, they'd do well to kill a bunch of its friends. This is the finding of a paper out this week in the journal Nature Communications, which describes the mutation rates of the common bacteria E. coli. Put simply, the study observed that mutation rates of the E. coli varied in proportion to the total number of bacterial "friends" a given bacterium had around it. It would then follow that, generally, the lonelier the bacterium, the better chance it has to develop resistance. You can see the problem.

To understand how this works, it helps to understand how bacteria communicate. First of all, they do in fact "talk," in a way: bacteria release signaling molecules, pheromones, that match up with receptors found on other bacteria. Once the pheromone binds with the receptor, it activates the transcription of certain genes in the receiver, in particular the gene responsible for production of the initial signaling molecule. The receiver then becomes a sender.

Within a group of bacteria, the result is a positive feedback loop in which more and more signaling molecules induce even more signals and eventually, a sort of critical mass is reached within the bacteria group where these signaling molecules are no longer being washed away as they would if only a small amount of pheromones were present. So, if a bacteria group is small, and the number of pheromones produced is small, the pheromones just dissipate, failing to induce more pheromone production. Past a certain population, however, there's enough of the signaling molecule present to overcome this dissipation, and the feedback process starts. This is how bacteria know they're in a real serious bacteria colony.

This has a name: quorum sensing. A quorum in this case would be the minimum number of bacteria needed to do a certain thing or things. When the bacteria Pseudomonas aeruginosa, for example, reaches a certain population threshold (the quorum), it goes into attack mode, multiplying rapidly, producing protective biofilms, and becoming virulent, e.g. attacking and suppressing the host's immune system while unleashing destructive enzymes. This is an infection and it's how bacteria kill as they colonize.

Which brings us back to antibiotic resistance. It turns out that when bacteria reach a quorum, they slow their rate of mutation dramatically. When the bacteria fall below a quorum, mutation rates increase and that means that resistance rates increase as well. One can imagine the increase in rates as a defensive posture for a bacterial colony that's smaller and thus more vulnerable. In terms of adaptation, these bacteria would need to be quicker on their toes, so to speak.

Dr. Chris Knight, one of the study's co-lead authors, confirmed this in an email. "[W]hen a bacterium is doing well, any mutation is likely to be bad, but when it’s doing badly, the risks of mutation may be outweighed by the possible benefits of an advantageous mutation. The problem is, how does a bacterium know whether it’s doing well or badly? One indicator might be that, if it has many other bacteria around it, it’s doing well, and if not it’s doing badly. In this way this change in mutation rates we see could perhaps provide the bacteria with an evolutionary advantage."

The implication should be obvious. A patient being treated with antibiotics is going to become a probable host for new antibiotic resistance. It's an ominous finding, but the discovery of this signaling mechanism may be good for antibiotic development in the long run. "You could imagine all sorts of ways that bacteria might exploit [this mechanism] in each other," Dr. Knight added. "[For example], deceiving rivals into not mutating when they would do better to mutate, or into having damaging mutations when they shouldn’t."

He noted that humans might be able to use the very same trickery, adding another, very needed arsenal to the race against resistant bacteria.