How penicillin-eating bacteria could help design new antibiotics
Throw antibiotics at bacteria and you expect them to die — not gobble them down. But there are some bugs that, paradoxically, need to eat antibiotics to live.
Now we know how they manage it. Researchers in the US and Europe unpicked the three-step process that let some bacteria dismantle and use penicillin for food.
They then engineered a bacterial strain to become a penicillin-eating machine.
The work, published today in Nature Chemical Biology, could one day help clean up antibiotics from farm animal waste and give chemists a new tool to design synthetic medicines, according to study co-author and Washington University microbe ecologist Gautam Dantas.
It’s no secret that we take antibiotics for granted today — a little too much.
With resistant bacteria already widespread, chemists must design new ways of stopping them.
We tend to think about antibiotics as a human creation, said Roisin McMahon, a structural biologist who works in drug discovery at Griffith University.
“But we sometimes forget that they’re abundant in the environment and of course, that’s where we discovered them in the first place — they’re naturally produced.”
Penicillin — the first antibiotic discovered — is perhaps one of the most famous and fortunate accidents in science.
Some 90 years ago, Scottish physician Alexander Fleming came back from holidays to a mess of a laboratory.
He found a fungus had crept into and contaminated some of his bacterial colonies while he was away.
Under the microscope, he saw that bacteria which had been invaded by the fungus didn’t grow.
Then Howard Florey, an Australian pathologist at Oxford University, and his team isolated and purified the bacteria-stopping compound produced by the fungus: penicillin.
The deadly “warhead” of the penicillin molecule is called “beta-lactam”. It weakens a bacterium’s cell wall, causing it to burst open.
Since penicillin’s discovery, chemists have found and created many more beta-lactam antibiotics. And in response, bacteria evolved resistance.
A decade ago, Professor Dantas knew little about antibiotic resistance, but was on the verge of his own serendipitous discovery.
Then a postdoctoral researcher at Harvard University, he was after bacteria that could thrive on plant compounds and produce biofuels.
In one of their experiments, he and fellow researcher Morten Sommer needed a negative control — a scenario where bacteria would not survive.
They thought: what better than giving them antibiotics?
“To our surprise, the negative control bacteria didn’t die — they flourished, some even more than our biofuel bacteria,” he said.
They weren’t the first to discover antibiotic-eating bacteria. Some strains were described back in the 1960s.
But with their biofuels work on the backburner, the pair published the first broad survey of soil-dwelling bacteria which not only shrugged off antibiotics, but thrived in their presence.
In the 10 years since, Professor Dantas has been trying to unravel bacteria’s tricks.
Finally, using four strains from his postdoc work, he and his colleagues figured it out.
Take penicillin. It’s a longish molecule, with the lethal beta-lactam area near the middle.
The first step antibiotic-munching bacteria need to do is dismantle the beta-lactam warhead.
A special enzyme — think of it as a special set of molecular scissors — snips one of the beta-lactam bonds, leaving the square hanging open and rendering it useless.
The same trick’s employed by a whole host of antibiotic-resistant bacteria — it’s not new.
But then, the antibiotic-eating bacteria use another enzyme to cut the penicillin molecule in two, ending up with one half with the disabled beta-lactam plus a molecule of phenylacetic acid.
It’s the phenylacetic acid that the bacteria attacks with another swag of enzymes to eat it.
To confirm the process, Professor Dantas and his team took a strain of Escherichia coli that could already eat phenylacetic acid, and inserted genes to give it the ability to carry out steps one and two.
Bingo! An engineered, antibiotic-eating bacterium.
Microbial clean-up crew
So why is building a strain of bacteria that demolishes penicillin interesting, and not terrifying?
“It’s because now you have the potential to bioremediate,” Professor Dantas said.
“One of the big problems of antibiotic use, whether it be in hospitals or in agriculture or aquaculture, is that once you use the antibiotic, they stick around.”
Some microbiologists suspect this is how resistance arises, he said: “We allow these antibiotics to go out in the environment and select more resistant bugs to survive along the way.”
By harnessing the power of an engineered organism that chops antibiotics, farmers could “mop up” any leftovers in animal waste.
Drug designers might find the enzymes handy, too, Professor Dantas said.
Lop the phenylacetic acid off penicillin and attach a bigger, bulkier molecule, and you might physically block bacteria from using their enzyme scissors on beta-lactam.
Finding new enzymes, too, may let chemists better produce the starting materials for new antibiotics, which can be an expensive process, Dr McMahon said.
“It’s a bit of an arms race — we tweak an antibiotic, the bacteria become resistant, we make another new one, and so on.
“If anything can make it easier, that’s only a good thing.”
For her, though, the work is also a reminder that these microbes have been around for billions of years.
Along the way, some started producing antibiotics while others mounted defences against them, such as finding ways to eat them.
“Bacteria have their own relationship with antibiotics, completely independent of how we use them in hospitals,” she said.
“We use antibiotics against bacteria, but of course they’ve been living with them much longer than we have.”