A synthetic antibiotic may help turn the tide against drug-resistant pathogens

A new antibiotic, synthesized at The Rockefeller University and derived from computer models of bacterial gene products, appears to neutralize even drug-resistant bacteria. The compound, named cilagicin, works well in mice and employs a novel mechanism to attack MRSA, C. diff, and several other deadly pathogens, according to a study published in Science.

The results suggest that a new generation of antibiotics could be derived from computational models. “This isn’t just a cool new molecule, it’s a validation of a novel approach to drug discovery,” says Rockefeller’s Sean F. Brady. “This study is an example of computational biology, genetic sequencing, and synthetic chemistry coming together to unlock the secrets of bacterial evolution.”

Acting on eons of bacterial warfare

Bacteria have spent billions of years evolving unique ways to kill one another, so it’s perhaps unsurprising that many of our most powerful antibiotics are derived from bacteria themselves. With the exceptions of penicillin and a few other notables derived from fungi, most antibiotics were first weaponized by bacteria to fight off fellow bacteria.

“Eons of evolution have given bacteria unique ways of engaging in warfare and killing other bacteria without their foes developing resistance,” says Brady, the Evnin Professor and head of the Laboratory of Genetically Encoded Small Molecules. Antibiotic drug discovery once largely consisted of scientists growing streptomyces or bacillus in the lab and bottling their secrets to treat human disease.

But with the rise of antibiotic-resistant bacteria, there is an urgent need for new active compounds — and we may be running out of bacteria that are easy to exploit. Untold numbers of antibiotics, however, are likely hidden within the genomes of stubborn bacteria that are tricky or impossible to study in the lab. “Many antibiotics come from bacteria, but most bacteria can’t be grown in the lab,” Brady says. “It follows that we’re probably missing out on most antibiotics.”

An alternative method, championed by the Brady lab for the past fifteen years, involves finding antibacterial genes in soil and growing them within more lab-friendly bacteria. But even this strategy has its limitations. Most antibiotics are derived from genetic sequences locked within clusters of bacterial genes, known as biosynthetic gene clusters, that function as a unit to collectively code for a series of proteins. But those clusters are often inaccessible with current technologies.

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