How bugs become resistant to the drugs

05 December 2016

Interview with

Dr Hendrik van Veen, University of Cambridge

How do bugs sidestep antibiotic assassination?  Hendrick van Veen from the An assortment of drugsUniversity of Cambridge works on how this happens and he told Chris Smith about one mechanism called an efflux pump...

Hendrick - Efflux pumps are really interesting ways by which bacteria can overcome toxicity of antibiotics.

Chris - Might one consider these efflux pumps to be a little bit like a bacterial vacuum cleaner, which sits in the cell and grabs stuff; detritus, dirt, molecules that shouldn't be there and just picks them up and throws them out?

Hendrick - Yeah. So antibiotics are compounds that can bind to membranes and then it can move into cells and bind on the inside of the membrane and from there they move on to bind to targets. And theses efflux pumps they are in the membrane and have binding sites that basically suck up antibiotics from the membrane and then throw it out.

Chris - So they sound like quite bad news if they're able to spread and propagate. Why can't we just make some molecules which are, effectively, antibiotics which will go in there and block these efflux pumps up?

Hendrick - Well, one of the reasons is we in our body also have multidrug efflux pumps and they're really important for the protection of organs, like the brain against toxic compounds. And so if we were able to make inhibitors of bacterial efflux pumps, there is a very good chance that these inhibitors will also block efflux pumps in our body.

Chris - Oh dear. So the whole premise of an antibiotic chemical which is exploiting differences between bacterial cells and human cells, that would be lost because if they are so similar to our own, then we end up causing harm to ourselves in the process of trying to kill the bug?

Hendrick - Indeed. That has been the strategy so far. I think these days people look in very great detail at the shape of these efflux pumps and from the structures, it might be possible to make new agents that are really selective for bacterial efflux pumps and not for the human ones.

Chris - So how do bacteria become resistant other than by having efflux pumps?

Hendrick - One important mechanism is a mechanism by which bacteria can modify the antibiotic of maybe degrade the antibiotic.

Chris - They could just break it down. How else?

Hendrick - You also have mechanisms where you have mutations in targets that actually may no longer interact with the antibiotic.

Chris - So in effect changing shape so the antibiotic molecule can no longer dock with whatever it was hitting before?

Hendrick - Yes. And also, sometimes, you have amazing mechanisms where bacteria produce a lot of targets and then some of these targets escape the actions of antibiotics. And then the pathways that normally lead to the synthesis of new building blocks for new cells still occur.

Chris - So basically they're just outcompeting the antibiotic because they make so much of the thing the antibiotic hits that there's just no way of getting enough antibiotic in to outcompete what the bugs doing?

Hendrick - Yes, indeed. I think it really shows that antibiotic resistance mechanisms co-evolved with the use of antibiotics as a way to compete with other organisms in the natural environment.

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