Resistance: bacterial defence against antibiotics

20 November 2017

Interview with 

Professor David Grainger, University of Birmingham

BACTERIA

Intestinal (gut) microbes (bacteria)

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Antibiotics are at the top of the agenda; it’s been “World Antibiotic Awareness Week” and, as the WHO have put it on their website: “The world is running out of antibiotics.  We need to take action to protect human health.” Well, right on cue, researchers at the University of Birmingham have used a new technique to uncover a host of potential new targets against which we may be able to produce new antibiotics to stem the rising tide of antibiotic resistance. David Grainger told Chris Smith what they've been doing...

David - The issue that we were interested in were the mechanisms that bacteria can use to protect themselves from antibiotics. One of the mechanisms that we’ve known about is a pump kind of mechanism, so if you imagine a sinking ship taking on water, a bit like a bacterial cell taking on antibiotics. A common mechanism is just to pump the water out of the boat, as it were, so the bacteria can pump the antibiotics out of the cell. So that was something we knew about, but we had an inkling that it was probably more complicated than that and that other things were happening at the same time and we wanted to try and figure out what those other things were.

Chris - So bacteria don’t just resort to one solution when someone throws antibiotics at them, you’re saying there’s probably multiple things that they do, one of which is to get rid of the antibiotics from within their cells, but there are others?

David - Yes, certainly. Bacteria very seldom rely on one line of defence. Broadly you often find that they’ve got multiple levels of a defence or a certain system to deal with the problem, so they’re very resilient.

Chris - What did you do to try and unpick, apart from pumping things out of their cells, what else bacteria can do?

David - We use a technique which is called chromatin immunoprecipitation and, I guess, you could think about it a little bit like a molecular fishing line, and we can use that molecular fishing line to hook out genes from the bacterial genome that are important for antibiotic resistance. An issue is, okay, we can sequence bacterial chromosomes, we can find out what all the genes are, but what we really need to know are which, out of those thousands of genes, which are the handful of genes that are important for antibiotic resistance. And that’s where this kind of molecular fishing rod came in so we could hook out the important genes and then work out exactly what they were doing.

Chris - What genes did you fish for?

David - We fished for genes that were a target for a protein called “the multiple antibiotic resistance activator.” That sounds complicated but it’s not. What this protein basically does is switch on the genes that you need to resist certain antibiotics, so by targeting these genes we could just identify the genes that we were interested in.

Chris - I see. So this gene turns on when it sees some antibiotics and that, in turn, triggers lots of defence mechanisms all at once by this master switch? So if you follow the scent of what that master switch is turning on, you can then work out what mechanisms the cells is invoking to defend itself?

David - Yes, that’s exactly right.

Chris - And what did you flush out?

David - We got, I think, it was just over 30 genes of interest, and two of them we focused on in detail. Going back to the analogy of the sinking ship, one of the sets of genes that we identified was important for kind of plugging holes in the cell. If you imagine the cell surface as being like the hull of a boat - it’s got holes in that’s letting in water or, in the case of the cell, letting in antibiotics, one of these gene systems, these sets of genes, was able to help plug those holes and stop the antibiotics from getting into the cell.

The other set of genes that we identified were important for repairing the DNA. Some antibiotics work by damaging the bacterial DNA, and we found that one of the sets of genes was important for repairing the damage that was caused.

Chris - Why does this help us in our present situation of facing an antibiotic apocalypse as some people have described it where we’re worried that, in the future, we may have not drugs left to treat things? Why does what you’ve found here help us to meet that challenge?

David - What we can probably do is that now we know about these defence mechanisms we can start to perhaps make new drugs that can target the defence mechanisms.So, if you knockout or hinder one of the defence mechanisms we would expect make the bacteria more sensitive to certain antibiotics. For example, if you take the genetic system that’s important for blocking the holes in the surface of the cell, you can imagine that if you could hinder that system, it might allow antibiotics to get into the cell more easily. It might allow different types of antibiotics to get into the cell more easily; perhaps ones that couldn’t get in there beforehand - things like that. So what we would like to do is target these defence systems and see if we can stop them from working.

Chris - Is that easy to do because is that not what antibiotic researchers have been trying to do ever since Florey and Fleming first came up with penicillin?

David - These are new target that we won’t have searched for drugs to hit before. They’re new system that we can screen for drugs against.

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