Antibiotics have been taking it on the chin lately. Not only has resistance to the medications been growing, but drug companies have been dropping antibiotic research programs because the drugs are difficult and expensive to make. Now, help is on the way. Researchers report today that they’ve found a way to churn out new members of one of the most widely used classes of antibiotics, called macrolides. The work could lead to new weapons against antibiotic-resistant infections, and possibly save millions of lives.
Macrolides, drugs that include erythromycin and azithromycin, were first developed in the 1950s. Since then they’ve become a bulwark against bacterial and fungal infections. Chemically, macrolides are giant rings containing 14 to 16 carbon atoms, with one or more sugar appendages dangling off the side. Bacteria synthesize them to fight off their neighbors. Yet bacteria didn’t evolve to make macrolides good drugs in people. So medicinal chemists—the group of researchers who actually build new drugs—start with the natural versions and tweak their bonds one at a time in an effort to make them safer and more effective. But in most cases it’s impossible to confine the changes to just one bond on a large molecule. When multiple bonds react, the result is an unwanted broad mixture of end products, none of which contain just the one specific change desired for making a better drug.
To solve that problem, Harvard University chemist Andrew Myers and colleagues adapted a divide-and-conquer strategy that they had applied to tetracycline antibiotics back in 2005. They started with three basic macrolide ring structures and broke each one down into eight molecular “modules.” They then carefully mapped out reactions needed to put the pieces back together. For two such linkers they even invented new chemical reactions to forge the bonds just so. This allowed them to tinker with the modules individually, and then reassemble them. By repeating the strategy over and over, they forged more than 300 entirely new macrolides.
When given to a panel of bacterial lab cultures, several of these compounds showed potent antibiotic activity against antibiotic-resistant microbes, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus, the team reports online today in Nature. Perhaps equally important, Myers says, is that all the reactions used for the assembly produce high yields of the final products. That’s essential, he notes, because bacteria don’t produce the starting material for the new compounds. So if any of them proves a valuable medicine, chemists will be able to synthesize large quantities of it cheaply from scratch.
“This is a great example of beautiful chemistry that will have a tangible societal benefit,” says Phil Baran, a synthetic organic chemist at the Scripps Research Institute in San Diego, California. Myers has set up a company, Macrolide Pharmaceuticals, to commercialize the work.