Bacteria are very good at evolving resistance to our drugs. Once all-powerful wonder-cures, antibiotics are steadily becoming less effective. If antibiotic resistance continues to spread, reports suggest that by 2050, 10 million people could die every year from infections we won’t be able to treat.
This is a serious problem. To solve it, we need to have a better understanding of the mechanisms that allow bacteria to evade drug treatment. And the science of how they do that is pretty incredible.
For example, bacteria can evolve pumps to bail antibiotic molecules out of their insides. Or they can produce molecules to neutralise antibiotics directly. And sometimes, they even mutate the structure of their own molecules, so that the antibiotics can’t bind to their targets.
But it doesn’t really make sense to think of bacteria as individual, lone survivors. Bacteria are always part of a community – one that’s dynamic, and constantly changing. For one thing, bacteria can share resistance genes between each other. For another, many bacteria live stuck together in communities called biofilms, often with a tough slime coating that protects the inner cells from the reach of antibiotics.
If you want to understand the mechanisms of resistance, you have to understand the interactions between different bacteria. And perhaps one of the most striking examples of this is ‘passive resistance’ – where cells with no resistance to antibiotics can indirectly reap the rewards from others that do.
This can happen when resistant bacteria secrete a neutralising molecule into the surrounding environment, clearing it of antibiotics and allowing susceptible strains to grow. But new research shows it can also happen when bacteria neutralise the antibiotics inside their own cells, acting like tiny decontamination factories for susceptible strains.
The findings, published in PLOS Biology, also describe something totally unexpected about this mechanism. In some cases, bacterial ‘freeloaders’ can actually outcompete their resistant neighbours – even though they have no special abilities themselves.
The researchers looked at Streptococcus pneumoniae, an opportunistic pathogen of humans that lives in the nose and throat. They treated the cells with the antibiotic chloramphenicol and found that, at a certain ‘sweet spot’ of bacterial densities, susceptible bacteria could coexist with resistant species, and sometimes even do better then them.
“It very much depends on how many resistant bacteria you have,” explains Dr Robin Sorg, lead author on the paper. “It’s all about the timing between nutrient consumption and antibiotic deactivation.”
At low cell densities, there simply aren’t enough resistant bacteria present to make a dent in the antibiotic levels, so the susceptible cells die. At very high cell densities, the resistant strains rapidly use up the available nutrients – so the susceptible cells don’t even get going.
But, at the sweet spot, there are enough resistant bacteria to clear the environment of the antibiotic, and the susceptible cells have enough time and resources to start growing. And because it takes extra energy for the resistant bacteria to neutralise the antibiotic, any cells that don’t carry this burden may have a slight advantage.
You can see this in the time-lapse video below, where the phenomenon is demonstrated in between two different pathogenic species: resistant Staphylococcus aureus and susceptible Streptococcus pneumoniae. At first, only the resistant cells grow (the bright green cells). But eventually, they pave the way for susceptible cells, which quickly explode in numbers.
Using mathematical modelling, the researchers also showed that in some situations, the susceptible cells do so well that they actually drive the resistant cells to extinction, by outcompeting them and using up all the nutrients. And without the resistant cells there to detoxify the environment, they ultimately become extinct themselves. Talk about biting the hand that feeds you.
The team then wanted to know whether this could happen in the real world – is the effect medically relevant? To find out, they ran an experiment on mice, infecting them with both resistant and susceptible strains of S. pneumoniae, and then treating them with the antibiotic chloramphenicol.
When they looked at the levels of bacteria in the mice afterwards, they found the same effect – treating with the antibiotic gave the susceptible cells an advantage, and in some cases they outcompeted the resistant cells.
It’s worth pointing out that this was a small study, but although far from conclusive, papers like this raise important questions about how resistance spreads in the real world.
“This might be one mechanism that adds to the dynamics of resistance development,” explains Robin. “Even if there is a small passive resistance effect, it means there is increased survival of susceptible cells – and increased opportunities for them to gain resistance.
“Additionally, you have the resistance genes encoded in the neighbouring cells. So if a couple of them burst, you have the perfect setting for gene transfer. [Passive resistance] could be one big factor that increases spreading of resistance genes.”