Developing antibiotic resistance is bacteria’s way of saying they miss their friends. Ok, probably not, but it is true that when population densities are low and isolated from each other, mutations speed up, including those that produce resistance.
In 2014, Dr Christopher Knight of the University of Manchester revealed that sparsely populated E. coli populations are three times as likely to mutate as those that are densely packed. Now Knight is senior author of a paper in PLOS Biology showing that this is not a trait unique to E. coli, but rather something universal to bacteria, yeast, and even viruses. To prove this, Knight and his colleagues analyzed 68 studies of 26 species, involving an estimated 2 trillion cells.
They found that evidence for this effect has been around for a long time – some of the studies they considered date back 70 years, but no one had seen the pattern. This may be because it lies in an unexpected direction. Stress can often increase mutation rates, and higher densities would, all else being equal, be more stressful.
The authors labelled the phenomenon "density-associated mutation-rate plasticity" (DAMP). First author Dr Rok Krašovec said in a statement: “What's exciting about DAMP is that it requires protein molecules that do the same thing in very different microbes, meaning that we can start to understand why mutation rates vary like this. This means that our results could be the first step towards manipulating microbial DAMP clinically as a way to slow the evolution of antibiotic resistance.”
For their experimental work, the authors focused on mutations that lead to antibiotic resistance, the consequence of microbial mutation we most urgently need to understand.
Even though DAMP occurs in all the species studied, the authors report: “We find that the degree of plasticity varies, even among closely related organisms.” In the most extreme case, mutation rates were 23 times lower at high population densities.
DAMP can also be controlled. The paper reports that in every case it was related to the scavenging of the nuceleotide 8-oxo-dGTP, which is known to induce mutations. Where other microorganisms are scarce, there is more 8-oxo-dGTP to go around. The authors found they could genetically manipulate DAMP in many species, potentially offering a path to controlling antibiotic resistance.
Exactly how this will be done remains unclear – encouraging a potentially dangerous bacteria to multiply in order to suppress mutations has obvious drawbacks. Nevertheless, anything that could provide a clue to tackling resistance is welcome. Knight noted: “According to the World Health Organisation (WHO), if resistance continues to rise, by 2050 it would lead to 10 million people dying every year.”