Pasteur said that luck only favors prepared minds (le hasard ne favorise que les esprits préparés).
Perhaps this was why when Alexander Fleming returned from vacation and found that a fungus had contaminated his staph culture, he didn’t just adapt.
Instead of throwing them in the trash, he noticed that near the fungus, the staph colonies had died.
This observation led to the discovery of penicillin, which ushered in the era of antibiotics.
And I can say that those who live in this period are privileged in the history of our species.
Antibiotics are substances with the exceptional ability to kill bacteria without harming the infected patient.
Along with vaccines, they are probably one of the most important scientific advances in medicine.
Bacteria can again be the leading cause of death for humanity
Before the era of antibiotics, bacterial infections were the leading cause of death on the planet.
That is why diseases such as plague, tuberculosis, leprosy and cholera are part of our history.
That seemed to come to an end when antibiotics hit the market.
But it wasn’t that easy. The first to warn was Fleming himself.
In his speech to the Nobel Prize winner in 1945, he warned that misuse of these molecules could select resistant bacteria.
However, in the early decades of the antibiotic era, a multitude of new molecules were discovered and treatments worked without any problems.
Therefore, antibiotics were used carelessly and in large quantities.
Today things have changed a lot. We haven’t found any new antibiotics in decades, and multi-drug resistant bacteria (which resist several different families of antibiotics) are our daily bread in hospitals.
In fact, in 2014, antibiotic resistance was estimated to cause 700,000 deaths each year, and that number would rise to 10 million deaths a year by 2050.
If we can’t stop resistance, bacteria will again be the main killer of humanity, and Louis Pasteur’s prophecy that microbes will have the final say will also be fulfilled (Messieurs, c’est les microbes qui auront le dernier mot).
The mistake of underestimating bacteria
How can we not predict the occurrence of multi-resistance and the loss of effectiveness of our treatments?
Basically because we underestimate the ability of bacteria to develop.
Far from the simple mutation and selection model that we believed governed the emergence of resistance at the beginning of the 20th century, bacteria have several much more powerful strategies for overcoming adverse situations.
One is the horizontal transfer of genes, which causes bacteria of different species to exchange DNA that may be useful to them.
This connects all bacteria that are exposed to a threat (e.g. in hospitals when they are treated with antibiotics) with solutions that come from other microorganisms from other parts of the world.
The other strategy that we couldn’t predict is the existence of an evolution accelerator in bacteria called an integron.
Integron is a genetic platform that allows bacteria to capture genes that provide new functions and that act as memories that store useful functions for the bacteria.
One of the key elements for the integron is that the genes that were useful at a given point in time but are no longer there are very little expressed. In other words, they mean low energy consumption for the bacteria.
This is fundamental because one of the reasons we believed bacteria would never be multi-resistant is because we thought resistance would mean high energy costs. The integron solves this by expressing only a few genes that it is not interested in.
However, this situation is not static: when the bacteria are attacked by antibiotics, the integron is activated and rearranges its genes to find the antibiotic resistance gene that is now killing it.
In short, the integron is like a bacterial memory that allows you to learn new functions, reduce energy consumption when those functions are not in use, and save them when they are needed again.
This led us to postulate the theory that integron allows bacteria to adapt when needed.
Integron in action
In our latest work, researchers from Oxford University (UK) and Complutense University Madrid (Spain) were able to see the integron in action and confirm this theory.
To do this, we built two almost identical integrons into the pathogenic bacterium Pseudomonas aeruginosa (a bacterium that causes infections of the respiratory tract).
Both integrons have three resistance genes in the same order, so the last gene does not confer resistance to gentamicin as it is poorly expressed (but if we put it in the first position of the integron this gene would give resistance).
The only difference between the two integrons is that the integrase does not work on one of them. Integrase is precisely the protein that is responsible for capturing and reorganizing the integron genes.
With two identical bacteria, with the exception of the integrase gene – the integron works in one and the other does not – it is possible to compare the ability to develop the resistance provided by an integron.
To do this, we forced several populations of these two bacteria in the laboratory to grow with increasing concentrations of this antibiotic.
Hence, we can assess their adaptability by measuring the number of populations that survive and become extinct as the concentration of the antibiotic increases.
In addition, we sequence the genomes of populations in low concentrations of antibiotics and in very high concentrations.
Our experiments clearly show that when integron works it allows more populations to survive with high concentrations of antibiotics than when it doesn’t.
The sequencing showed that the integron at the beginning of this evolutionary race randomly reorganizes its resistance genes and thus creates genetic variability very quickly. And antibiotic choices can act on this variability.
This is essential at higher concentrations, where we only found bacteria that brought the gentamicin resistance gene to the first position of the integron and thus managed to increase its resistance.
Going forward, our research will help develop interventions that will reduce resistance and help us contain this silent pandemic.