Antibiotics — the miracle drugs of the 20th century — are beginning to fail. The latest evidence of this came in May, when a pathogen surfaced in Pennsylvania containing a gene that, if and when it spreads, would create bacteria that are invulnerable to every available drug.
The solution to the looming problem is simple, if hard to implement: First, we need to be far more conservative about how we use antibiotics in order to slow the development of resistance and prolong their usefulness; second, we need to find ways to create new antibiotics that bacteria can’t yet resist.
To that end, last month Harvard chemist Andrew Myers published a study in Nature describing a novel method for creating fully synthetic, designer versions of specific antibiotics — drugs that can be tweaked, maybe endlessly, to outwit the resistance mechanisms that develop in nature.
“When you build these things from scratch, your ability to make changes anywhere you want [on the molecule] is almost unlimited,” says Myers.
Most antibiotics we have today were found in nature. That’s the case with penicillin, which was discovered serendipitously in 1928 and first mass produced in the 1940s. It’s true of other powerful classes of antibiotics as well, like tetracyclines, which were first isolated from a microorganism found in a field of timothy wheat, and macrolides, like erythromycin, which was discovered in the late 1940s from a microorganism found in a soil sample from the Philippines.
Many naturally occurring antibiotics are not ideal as drugs in humans, so for decades, pharmaceutical companies have sought to improve them by using chemistry to modify the natural products to improve their safety and efficacy.
Macrolides and tetracyclines are the focus of Myers’s work. They’re especially powerful drugs that can kill a broad spectrum of pathogens, but they’re also large, complicated molecules that are difficult to construct entirely out of industrial chemicals. And without being able to do that, chemists are limited in the ways they can modify them.
“Chemists have been trying to develop practical routes to synthesize structurally complex antibiotics for 50 to 60 years, in some cases largely without success,” says Myers.
Previous efforts to synthesize these kinds of drugs have been laborious, involving 50 or more steps, which makes them impractical for production on an industrial scale. Myers has developed a shortcut. Instead of a linear chemical process, in which A is turned into B is turned into C is turned into D and so forth (with the final result, many steps later, being the drug), he’s developed a method for synthesizing eight simple building blocks that can be combined to quickly create a huge variety of molecules within a drug class.
“Andy has been really revolutionizing this seemingly old and not terribly exciting approach, where he can produce antibiotics from scratch,” says Kim Lewis, director of the Antimicrobial Discovery Center at Northeastern.
Myers has commercialized his method in two companies based in Watertown, Tetraphase Pharmaceuticals, founded in 2005, and Macrolide Pharmaceuticals, founded in 2015. The two companies have developed thousands of unique molecules — and continue to come up with dozens of new ones each week — but so far, they have no approved drugs. Tetraphase’s flagship drug, eravacycline, has had one successful phase 3 clinical trial, for complicated intra-abdominal infections, but failed a second phase 3 trial in complicated urinary tract infections last fall, which caused the company’s stock to crash.
Even if Myers succeeds in creating fully synthetic antibiotics, research will not stop there. It is not uncommon for resistance to develop to new antibiotics, sometimes within just a few years — a rate of obsolescence that even the best drug discovery programs will find challenging to keep up with.
“We’re just throwing these drugs down the drain and breeding resistance for no good reason,” says Michael Gilmore of Harvard Medical School, who studies antibiotic-resistant infections and is optimistic about Myers’s technology. Gilmore points to the particularly excessive use of antibiotics in animal feed as a main factor promoting resistance.
But if overuse can be curbed and new drugs can be discovered at even a modest pace, there may be no reason that the much-feared antibiotic apocalypse has to come to pass.
“You would think that at some point we’ll run out of ideas or options, and that may be the case, but it’s kind of amazing, with rather limited tools, some of these classes of antibiotics have been re-greened for decades,” says Myers. “I think there are many new powerful antibiotics to be discovered.”
Kevin Hartnett is a writer in South Carolina. He can be reached at firstname.lastname@example.org.