He said Pasteur that luck only favors prepared minds (le hasard ne favorise que les esprits préparés). Perhaps for this reason when, on returning from vacation, Alexander Fleming a fungus was found to have contaminated his staph cultures, he just didn’t settle. Instead of throwing them in the bin, he observed that the staph colonies had died near the fungus.
That observation led to the discovery of the penicillin, which inaugurated the it was antibiotic. And believe me if I tell you that those of us who live in this age are privileged in the history of our species.
Antibiotics are substances with the extraordinary ability to kill bacteria without harming the patient suffering from the infection. They are probably, along with vaccines, one of the most important scientific advances in medicine.
Bacteria will once again be the first cause of death for humanity
Before the antibiotic era, bacterial infections were the leading cause of death on the planet. That is why diseases such as the plague, tuberculosis, leprosy or cholera are an inherent part of our history. This seemed to come to an end when antibiotics burst onto the scene.
But it wasn’t that simple. The first to notice was Fleming himself. In 1945, in his Nobel Prize winning speech, he warned that the misuse of these molecules could select resistant bacteria. However, during the first decades of the antibiotic era, a multitude of new molecules were found and the treatments worked without problems. So antibiotics were used carelessly and in massive quantities.
Today things have changed a lot. Decades ago we did not find new antibiotics and multi-resistant bacteria (which resist several different families of antibiotics) are our daily bread in hospitals. In fact, in 2014 it was estimated that antibiotic resistance caused 700,000 deaths a year and that that number would grow to 10 million deaths each year by 2050.
If we fail to curb resistance, bacteria will once again be humanity’s number one killer, and Louis Pasteur’s prediction that microbes will have the last word (Gentlemen, the microbes will have the last word).
The mistake of underestimating bacteria
How is it that we were unable to predict the appearance of multidrug resistance and the loss of efficacy of our treatments? Well, fundamentally, because we underestimate the ability of bacteria to evolve.
Far from the simple model of mutation and selection that we believed in the early twentieth century that governed the emergence of resistance, bacteria have multiple, much more powerful strategies to overcome adverse situations.
One of them is horizontal gene transfer, which causes bacteria of different species to exchange DNA that may be useful to them. This connects any bacteria that face a threat (such as those in our hospitals when treated with antibiotics) with solutions that have originated in other microorganisms from anywhere else on the planet.
The other strategy that we failed to predict is the existence of a evolutionary accelerator in bacteria called integron. The integron is a genetic platform that allows bacteria to capture genes that provide new functions, acting as memories that store functions that are useful to the bacteria. One of the keys to the integron is that genes that were useful at one point but are not so useful are expressed very little. That is, they represent a low energy expenditure for the bacteria.
This is fundamental because one of the reasons why we believed that bacteria would never be multi-resistant is that we think that resistance would entail a high energy cost. The integron solves it by expressing little of the genes that do not interest it.
However, this situation is not static: if the bacteria are attacked by antibiotics, the integron is activated and rearrange your genes to find the antibiotic resistance gene that now he’s going to kill her.
In short, the integron is like a bacterial memory that allows learning new functions, reducing energy expenditure when these functions are not used, and remembering them when they are needed again.
This led us to postulate the theory that the integron contributes to adaptation on demand to the bacteria.
The integron in action
In our latest work, researchers from the Universities of Oxford and Complutense de Madrid have been able to see the integron in action and confirm this theory. For this we have built two integrons that are almost identical in the pathogenic bacterium Pseudomonas aeruginosa (a bacterium that causes respiratory infections).
Both integons have three resistance genes in the same order, so that the last gene does not confer resistance to gentamicin because it is poorly expressed (but if we placed it in the first position of the integron, this gene would confer resistance). The only difference between both integrons is that integrase does not work in one of them. Integrase is precisely the protein that is responsible for capturing and rearranging the genes of the integron.
Using two identical bacteria except for the integrase gene – in one the integron works and in the other it does not – the ability to develop resistance provided by an integron can be compared.
To do this, in the laboratory we force multiple populations of these two bacteria to grow in increasing concentrations of this antibiotic. Thus, we can assess their ability to adapt by measuring the number of populations that survive and the number of populations that become extinct when the concentration of the antibiotic increases.
Furthermore, we have sequenced the genomes of the populations at low concentrations of antibiotics and at very high concentrations.
What our experiments clearly show is that when the integron works allows more populations to survive at higher concentrations of antibiotic than when it does not work. Sequencing has shown that at the beginning of this evolutionary race the integron randomly rearranges its resistance genes, generating genetic variability very quickly. And selection by the antibiotic can act on this variability.
This is key at higher concentrations in which we exclusively find bacteria that have moved the gentamicin resistance gene to the first position of the integron and have thus managed to increase its resistance.
In the future, our research will help to design interventions that decrease resistance and help us stop this silent pandemic.
José Antonio Escudero. Microbiology Teaching and Research Staff, Complutense University of Madrid.
This article was originally published on The Conversation.