It’s World Antibiotic Awareness Week, with scientists and the World Health Organization this year focusing on the theme of “Spread Awareness, Stop Resistance” to raise global understanding of antibiotic and antimicrobial resistance.
The fear is that continuing overuse and abuse of antibiotics will render them much less effective, because it is driving exponentially-increasing levels of bacterial resistance.
For a newly-emerging resistance function to survive, there needs to be some selection pressure for it - that is, bacteria with that function gain something by keeping it around. If there is no selection pressure, it will just fizzle out.
By using antibiotics inappropriately, we maintain a selection pressure for the bacteria to evolve resistance, effectively setting up a scenario in which the resistant ones will have an advantage over the non-resistant ones, and start to dominate the population.
The more we misuse antibiotics, the faster this will happen. Moreover, bacteria are really good at trading genes to each other - so, by using antibiotics when the disease-causing bacterium is not there, we still massively increase the chance that a different species will become resistant and then pass the resistance gene to the dangerous bacterium.
In addition to not using antibiotics when not needed, we can minimise the risk of that happening by using compatible combinations of antibiotics, because it is far less likely that a bacterium will serendipitously evolve two new functions at once.
For example, even if one cell in a billion gains a chance mutation that improves resistance to an antibiotic, if a pair of antibiotics is used it will still be killed by the second antibiotic. To avoid that, it would need to gain two chance mutations at once, and the odds of that happening are one in a billion multiplied by a billion - an unfathomably unlikely one-in-a-quintillion.
DNA is the information store in cells that acts as the genetic blueprint for life. The information encoded by individual genes in our DNA is used to build individual proteins - a vast number of them, which play diverse roles in cells.
Many of the most essential proteins are enzymes, which are tiny nanomachines that perform virtually all of the chemistry of life, including replicating the DNA and helping to build other proteins.
While it has traditionally been thought that each enzyme was contributing a very specific function to our cells, evolutionary history is considerably less straightforward and simple than that. It’s a noisy and tumultuous affair, and a function that is critically important for a cell today may have been virtually irrelevant millennia ago.
What has become clear is that enzymes with some capacity to “moonlight”, i.e. perform additional jobs beyond their current primary role, can buffer cells against new stresses that arise. If the new stress persists, the enzyme can adapt, honing their new skills and turning the moonlighting job into a fixed full-time role.
This type of enzymatic career change can be particularly important for bacteria, which cannot run away from new stresses but must either evolve to meet the challenge or risk extinction.
A classic example of this is the development of antibiotic resistance. In complex environments such as soil, which can harbour more than 10,000 different bacterial species per gram, microbes collectively produce a bristling array of antibiotics as weapons. These enable them to battle with other species competing for the same limited resources.
Bacteria that can withstand the onslaught of a new antibiotic have a competitive advantage in this life-or-death struggle. A moonlighting enzyme which happens to be able to detoxify a particular antibiotic may provide that critical edge.
In natural environments, bacteria are confronted with an ever-changing host of enemies that all make different antibiotics, so there is seldom the sustained pressure required to adapt an amateur moonlighting enzyme into an antibiotic-resistance specialist.
But humans have changed the game by repurposing nature-derived antibiotics to treat clinical infections. Suddenly, antibiotics are being produced and used on a scale the world has never seen before. If used inappropriately, say by patients who fail to complete a course, then bacteria containing a partially-effective moonlighting enzyme may survive and move one step closer to developing full immunity to that antibiotic.
Our team in the Microbial Biotechnology Lab at Te Herenga Waka–Victoria University of Wellington is being supported by the Royal Society Te Apārangi’s Marsden Fund to investigate how entirely new forms of antibiotic resistance can develop from moonlighting enzymes.
While studies like this are usually performed by choosing a single disease-causing bacterium and growing it over many weeks in the presence of incrementally-escalating doses of an antibiotic, we are focusing on soil as a rich model environment and purifying all of the DNA from the thousands of bacterial species that reside there.
This gives us access to the collective set of genetically-encoded enzymes, and we have developed a unique way of breaking this DNA up into small gene-sized fragments and maximising the amount of protein they will produce when transferred into E. coli, a tame laboratory bacterium.
From this we are able to detect very weak moonlighting activities that help defend their new E. coli home against an antibiotic challenge. We can then use artificial evolution techniques to evaluate whether these have the propensity to adapt into dangerous levels of antibiotic resistance.
Of course, we have to be very careful in doing so, as we want to understand the spread of antibiotic resistance but not contribute to it! All our work is conducted under the same physical-containment conditions as used to study disease-causing bacteria that are already antibiotic resistant.
Our work also provides insights into how readily resistance to new antibiotic drugs might arise in the clinic, and the most likely way or ways for this to happen. This can in turn inform possible counter-measures.
For example, we have tested a promising new antibiotic candidate called niclosamide, which several research teams have shown bacteria struggle to become resistant to. Concerningly, we have found a type of enzyme that is common in soil bacteria and can readily be evolved to confer high-level niclosamide resistance.
The good news is, as this enzyme evolves to make bacteria more resistant to niclosamide, it makes them more sensitive to another common antibiotic, metronidazole. So, by administering metronidazole with niclosamide, doctors should be able to prevent this form of resistance arising.
This would be an encouraging step in our crackdown on the moonlighters.
Professor David Ackerley is a microbiologist and enzyme engineer in Te Kura Mātauranga Koiora–School of Biological Sciences at Te Herenga Waka–Victoria University of Wellington.
Read the original article at Newsroom.