In future, the most effective antibiotics might be those that don’t kill any bacteria. Instead the drugs will simply prevent the bacteria from talking with one another.

Drug-resistant bugs are winning the war against standard antibiotics as they evolve resistance to even the most lethal drugs. It happens because a dose of antibiotics strongly selects for resistance by killing the most susceptible bacteria first.

If, however, researchers can identify antibiotics that neutralise dangerous bacteria without killing them, the pressure to evolve resistance can be reduced. One way to do that is to target the constant stream of chatter that passes between bacteria as molecular signals.

Critical mass

Individual bacteria monitor the concentration of signalling molecules, and when it reaches a certain level, change their behaviour. That concentration provides a rough indication of when the number of cells in a particular population has reached a certain critical mass – known as a quorum.


When a quorum is reached, pathogenic bacteria shift from a benign state and begin attacking the host by secreting toxins.

But hacking the bacterial communication system could make it possible to prevent this transformation, and leave the cells waiting in a safe form for an attack signal that never comes. That would give the immune system extra time to naturally clear the bacteria from the body, says David Spring at the University of Cambridge, UK.

His research group has now developed an artificial molecule that could lead to a treatment to destroy the quorum signals sent out by many bacteria, including Pseudomonas – a bacterium that can lead to life-threatening conditions such as meningitis, and that is the primary cause of mortality in individuals with cystic fibrosis.

Fleeting target

The group is working with Martin Welch, also at Cambridge, to design an antibody that will act as an enzyme and speed up the natural decay of the signalling molecules. This could ensure that the bacteria never receive the command that triggers a change in behaviour.

That antibody would have to be able to bind to a short-lived transitional chemical formed during the natural breakdown of the signalling molecules, and could then chaperone them to an early demise.

This poses a tricky problem for the researchers, as the transitional chemical is too unstable to use in tests of suitable antibodies. “Transitional states have fleeting lifetimes and cannot be isolated,” says Spring.

To get round this, the team has come up with an artificial mimic to take its place. Because they can’t study the transitional form’s structure directly, their artificial version is a best estimate based on computer models.

Needle in a haystack

Initial tests, though, suggest the mimic is a close match for the real chemical.

At the beginning of the decade, Lian-Hui Zhang‘s team at the University of Adelaide in Australia identified a bacterial enzyme, AiiA, that naturally destroys quorum signal molecules (Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.060023897).

This enzyme cannot be used for human treatment because it is attacked and destroyed by the immune system.

Spring’s team put AiiA in a test tube with a ready supply of the quorum signal molecule and measured the rate of the breakdown reaction. When they added a quantity of their artificial molecule to the mix, the reaction rate dropped because some of the enzyme latched onto the artificial molecule instead – it would only have done this if the molecules were very similar.

Because of that success, the team will now begin searching through an extensive library of real and artificial human antibodies held at Cambridge to identify any that lock onto their artificial molecule. It might be some time before a good match is found, says Spring – the library contains some thousand billion antibodies.

Journal reference: Chemical Communications (DOI: 10.1073/pnas.060023897)