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New method for building antibiotics could produce 'thousands' of drug candidates

It's too early to tell if these compounds will help fight drug resistance

theglobalpanorama

A new method that lets scientists make antibiotics from scratch could lead to the development of thousands of new drug candidates, according to a study published today in Nature. But some experts caution against getting too excited; it's far too early to tell if the method will help in the fight against antibiotic resistance, they say.

In the report, researchers describe a new technique for creating macrolides — a class of antibiotics that's used to fight off pneumonia and gonorrhea, among other diseases. Normally, antibiotics in this class are made by modifying another antibiotic called erythromycin. But that approach is limiting for chemists because there are only so many changes that they can make to a complex compound.

The technique yielded over 300 new antibiotic candidates

That's why the method described in today's study is interesting: it lets researchers develop potential antibiotics without using erythromycin as a starting point. And that's important because physicians need more diverse antibiotics that can help fight antibiotic resistance, says Andrew Myers, a chemist at Harvard University and a co-author of the study. Already, the technique has yielded over 300 antibiotic candidates, including some that are active against resistant strains of bacteria, he says.

But some experts point out that it’s too premature to say whether the method can be used to overcome resistance because scientists don’t yet know if these drug candidates will be safe enough to use on humans. In addition, the researchers haven't yet looked at how quickly bacteria develop resistance to these novel compounds. That means that right now, there's no way to tell if the candidates are better than existing macrolides.

Resistance develops when bacteria encounter antibiotics in doses too small to kill them, and that can have very serious consequences. Each year, about two million people in the US become infected with antibiotic-resistant bacteria — and 23,000 people die as a result, according to the CDC. To overcome resistance, health officials have launched campaigns aimed at reducing the overuse of current antibiotics, both in hospitals and in farms, where they’re given to animals to avoid disease and make them grow faster. But many researchers think that discovering new antibiotics — either new classes of drugs or new ways to make variations on existing drugs — will be a crucial part of stopping resistant strains.

Scientists can make an "almost incalculably large number of antibiotic candidates"

The technique described by Myers and his team assembles an antibiotic using eight "building blocks" made from industrial chemicals — each of which can be modified individually. He likens the process to using different factories to make components of a cell phone. Because each component is separate, it's a lot easier to make changes to each of them, he says. That way, the method can be used to "synthesize an almost incalculably large number of antibiotic candidates," Myers says. "To say tens of thousands would not be an exaggeration," he adds.

To demonstrate the technique's effectiveness, the researchers produced exact replicas of existing antibiotics. They also produced new macrolides — including two that were moderately active against the bacteria MRSA, which is resistant to four existing antibiotics in that class. "We have a tool that gives us the best possible opportunity to find the next macrolide antibiotic for future generations," Myers says.

"It does seem like a clever way to generate novel compounds," says James Johnson, an infectious disease researcher at the University of Minnesota who didn't work on the study. But the study doesn't clarify how useful these new compounds will be. "What's lacking is compelling evidence that the approach can lead to better antibiotics," meaning ones that can overcome resistance or ones that can be used in lower doses, he says.

Kim Lewis, director of the antimicrobial discovery center at Northeastern University, also questions the utility of these compounds in overcoming antibiotic resistance. The best way to avoid resistance is to create entirely new kinds of antibiotics, he says. However, in this case, the method yields variants of macrolides, which might be useful for medicine in general, but "isn't a terrific solution to resistance," he says. That's because some bacterial strains are tolerant to new drugs simply because they've been exposed to existing antibiotics — a phenomenon called "cross-resistance."

Making variants of exciting drugs "isn't a terrific solution to resistance."

Slava Epstein, a microbial ecologist also at Northeastern University, was more blunt. Resistance to variants of macrolides develops fast, he says, so it's important that researchers find out how quickly a pathogen develops resistance to these new compounds in the lab. "I am surprised the reviewers of their manuscript did not ask for such simple data of such importance," Epstein says. It's also unclear from the study if these new compounds are toxic to human cells. "My point is, it is way too early to say if the synthetic efforts are any better than [modifying existing antibiotics], which is criticized in the paper, or any better than discovery from natural sources, which the study doesn't discuss."

In response, Myers says that the answers to many of these questions will come later. "These are studies one conducts further down the line towards antibiotic development," he says. Today’s study is really just about the development of a new drug discovery platform. "We prepared [around] 350 compounds — which is actually a pretty large number by today’s standards," Myers says. "So it is evident that we have just scratched the surface of what we can achieve."