Antibiotic resistance: an arms race going on millions of years

In 2012, a team of microbial scientists, curious about the origins of antibiotic-resistant bacteria, decided to take samples from the walls of a deep, ancient underground cave system beneath the modern US state of New Mexico. 

The maze-like complex of Lechuguilla cave stretches for more than 200 kilometres, and much of it is sealed from aboveground by an impermeable rock layer known as the Yates Formation. So, it was the perfect place to hunt for microbes unsullied by the modern world. 

What they found was both startling and spooky: the microbiome of the cave samples contained bacteria that were resistant to at least 14 different antibiotics currently on the market, even though they had been isolated for more than four million years.

Given that antibiotics were first used clinically after Alexander Fleming cultured Penicillium moulds in 1928, antibiotic resistance is generally thought of as a distinctly modern problem – and there’s no doubt our use and abuse of these wonder-molecules have created a huge and growing issue. 

recent study reported in The Lancet suggests more than 1.2 million people died in 2019 as a direct result of antimicrobial resistance. By some estimates, the death toll could reach 10 million per year by 2050 if nothing is done (by contrast, about  eight million people die from cancer each year). The World Health Organization identifies resistance as one of the biggest threats to global health. 

Tony Velkov, an Associate Professor in biochemistry and pharmacology at the University of Melbourne, says not enough attention is being paid to finding answers from nature; more specifically, the organisms that make their own, naturally occurring antibiotics in a dynamic environment.

“Lessons from nature, I call them,” Velkov says.

The majority of antibiotic medicines used clinically today are derived from natural antibiotics produced by microbes in soil and which attack rival microbes, as part of a miniature war over precious resources.

Indeed, Fleming’s discovery of the Penicillium mould’s antibacterial qualities was entirely by accident, says Velkov.

“He was growing a bacterium called Staphylococcus aureus, and he decided to go on a long weekend and left the plate on the bench,” he says. “He came back about a week later and he found this mould growing in one corner of the plate, and he found the bacteria that he’d been growing were scared of this mould, and they were all dying or keeping away from it.”

Fleming’s famously understated remark upon discovering this strange antibacterial interloper was: “That’s funny”. 

Velkov is particularly fascinated by the function of antibiotics in nature, as part of epic microbial conflicts taking place at every moment. A big part of his work is looking at a pugnacious little soil microbe called Paenibacillus polymyxa, which is able to kill gram-negative bacteria that enter its territory by producing polymyxins, a particularly aggressive type of antibiotic.

“Polymyxin is used in hospitals when you’re really, really sick, because it’s pretty toxic,” he says. For that reason, it’s often a medicine of last resort, which means it hasn’t had as many opportunities as other more common antibiotics, to trigger the evolution of antibiotic resistance traits in pathogens.

Nonetheless, polymyxin-resistance genes have been identified in bacteria across Asia, Africa, Europe, North and South America and Oceania. If the power of polymyxins is usurped by these resistant pathogens, it could spell disaster for people suffering from drug-resistant bacterial infections.

So, Velkov is trying to learn how to create new polymyxins, by mimicking soil-based battles.

“I get the bacterium that makes that [polymyxin], and then I challenge it,” Velkov says. “I grow it opposite the bugs it hates, and they fight each other.”

If it sounds a bit like a pathogenic boxing match, Velkov says that’s much like what he observes.

“They actually have a bit of a battle,” he says. “You’ll see the one that makes the antibiotic starts growing towards the bacteria to push it out of the territory [the petri dish with nutrients on it], and then it secretes the polymyxins to kill it.

“But the bug, the human pathogen, often fights back secreting stuff to kill the antibiotic-producing microbes.”

How does all this lab-based micro-fighting translate to the real-world problem of resistance?

According to Velkov, in medicine, humans mostly focus on producing one type of antibiotic at a time. But in the “wild”, he says, microbes can often produce a whole bunch of subtly different substances in the fight.

“In the petri dish, when these guys are fighting each other, they make really different ones,” he says. “Ones we haven’t seen or discovered, they respond in ways we haven’t looked at.”

In his research lab, Velkov says he’s discovered a number of new polymyxins, including one that’s in clinical development.

So, by staging these kinds of epic battles in miniature in the laboratory, can we stave off antibiotic resistance altogether? According to Velkov, probably not. But we can optimise our participation in the evolutionary arms race.

“You’re never going to make it go away,” he says. “This has been going on for millions of years.”

But the hope is that by learning from how these microbes behave in nature, we can at least try to keep pace. 

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