Stephen Baker, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam
Contrary to prevailing wisdom, antibiotic-resitant typhoid bugs grow better than their unmutated counterparts...
Chris - Now so the dogma goes, when bugs mutate to out-manoeuvre an antibiotic, theyíre forced to surrender some of their reproductive fitness. So, they reproduce less well than non-resistant or wild type microbes. So, when Steven Baker found that his antibiotic resistant mutant bugs in fact grew much better than their parents, he originally thought the results must be wrong.
Steven - So, Iíve had a long term interest in typhoid fever, a disease thatís quite common in some developing countries caused by bacteria, Salmonella typhi. Weíve been interested in working on how the organism becomes and sustains resistance to a number of different drugs that are used to treat it.
Chris - How widespread is resistance to the first line treatments?
Steven - First line treatments, we no longer really use. The majority of places would have widespread resistance to the common treatments that were being used 10Ė15 years ago. And thereís been more common use of a group of drugs called fluoroquinolones, but resistance to that group of drugs has been spreading quite rapidly where typhoid is common.
Chris - So, how did you do this study?
Steven - What we wanted to do is calculate whether we could explain why the organism seemed to spread very rapidly and whether it was merely dependent on the use of fluoroquinolones. So, we made organisms that were resistant to the drugs that weíre interested in by introducing single mutations that we know are associated with the change in resistance to fluoroquinolones, and then we basically competed them with one another. The best way to describe it would be to simply to do a drag race with bacteria over a 150 generations to see which ones are the winners.
Chris - I like the analogy. So, the idea here is that youíre comparing whether having these mutations, which on the one hand give the bacteria the ability to resist the antimicrobial drug and whether that encumbers them or impairs them when theyíre growing against other microbes which donít have that disabling mutation.
Steven - Absolutely, yeah. The scientific dogma really is that organisms that have these mutations or resistant to antimicrobials are less fit because organisms are adapting to work in a particular environment. So, thatís what we really thought when we started the experiments, and what we were trying to do is calculate that negative effect.
Chris - So, you expected when you did this that the ones you are mutating were going to grow less well, and you just wanted to know by how much.
Steven - That was our original working hypothesis, yeah. So, we have gathered quite a lot of data on the circulation of these strains in different countries, and there is one particular strain that is dominant, and we thought that that would have a selective disadvantage.
Chris - And is that what you saw?
Steven - No. In fact, we saw quite the opposite. And at first, we were quite concerned about our results and I had several long conversations with a student of mine about the way the experiments have been done. We repeated them to the point of insanity really, to make sure that what we were seeing was correct, and what we found is, some of the organisms actually outgrew or out-competed the parent strain.
Chris - So, this flies in the face of perceived wisdom by becoming resistant to the antimicrobial agent, these bugs are fitter, they grow better.
Steven - Thatís exactly what data showed and in fact, to emphasise that a little bit more, what we found is that we induced strains with single mutations, double mutations, and also triple mutations. So, one, two, or three different mutations in sites that drugs actually target. And we found if you have two mutations in a particular gene, that actually exaggerates the effect.
Chris - So, why do you think that bugs haven't naturally evolved to have those changes in their DNA?
Steven - So, thatís a very good question and itís something that we donít really have a great answer for. The one limitation of our experiments is that we did it in a laboratory. What we donít really know is how that relates to whatís going on in the natural environment and there may be other ecological niches that we canít replicate in a laboratory or we donít quite understand that maybe those organisms may behave differently.
Chris - Do you think that in some way, you need the antibiotic agent there in order to maintain the stability of that change? Is it that itís good in the short-term but in the long-term, it does have some disbenefit and you just didnít do the experiments for long enough to see it?
Steven - That may be the case. I also think that potentially, whatĎs happened is that these strains may have been circulating for some time, even before the introduction of the drugs and then the introduction of the drugs formed a greater selective pressure for these organisms and then because of their selective advantage, theyíve become sustained in the population.
Chris - What do you think the implications are for medical usage of these sorts of agents and therefore, what weíre dubbing these days Ė better antimicrobial stewardship Ė making sure that we minimise the chances of antimicrobial resistance occurring?
Steven - What it says for typhoid, as the resistance is increasing thereís some question about how long we can continue to use these agents for. These organisms are so common that therefore if we stopped using fluoroquinolones now, then actually, we probably wouldnít remove these organisms to the extent that we could start using fluoroquinolones again at any time soon.
Chris - Sobering finding, isnít it?