Brandeis Magazine
The Molecule Hunter
Mo Seyedsayamdost ’01 is on a quest to increase a dwindling arsenal of lifesaving antibiotics.
By David Levin

Mo Seyedsayamdost ’01 (Photo Credit: Todd Reichart)
The bacterial world is not a peaceful place. Every day, its microscopic critters wage a fierce existential battle, fending off waves of attacking microbes hell-bent on conquering their neighborhood.
It’s no surprise, then, that many species of bacteria have evolved unique ways to defend themselves. Send invading microbes into a group of Streptomyces bacteria, for instance, and the colony will spit out a molecule that quickly kills off the assailants.
“It’s a kind of chemical warfare that happens in every bit of soil, or water, or other microbial environment,” says Mo Seyedsayamdost ’01, professor of chemistry and molecular biology at Princeton University.
Though these chemical weapons are bad news for invading microbes, they can have the opposite effect when given to sick humans, clearing up serious infections in days. In fact, Seyedsayamdost says, most commercial antibiotic drugs, used to treat ailments from pneumonia to syphilis, are based on the molecules that a handful of microbial genera use to survive.
Scientists have identified only a couple hundred molecules that have given rise to these life-saving drugs. Yet the microbes that create them can also make thousands of other molecules, and the vast majority of these molecules are still unknown or unstudied. What incredible new lifesaving abilities might they hold?
Seyedsayamdost and his lab are leading the way in identifying these new molecules. And the discovery of new molecules is more urgent than ever. Over the past two decades, some common microbial strains have developed immunity to widely used drugs. Treating infected patients has become a serious challenge. According to the Centers for Disease Control and Prevention, roughly 2.9 million people suffer unnecessarily from illnesses caused by antibiotic-resistant strains each year, and at least 48,000 of them die.
“To put it as simply as possible, we are in the antibiotic discovery business,” Seyedsayamdost says. “All these traits that chemists work hard to code into synthetic drugs are sometimes just there in naturally produced molecules, because it’s their evolutionary purpose. So it gives us a much better starting point for drug discovery and development than a random synthetic molecule.”
Microbes have had a long time to develop and test their chemical defenses. Over millions of years of evolution, they’ve perfected molecules that do narrowly focused tasks — like latching onto a particular chemical receptor, permeating certain cell membranes, or inhibiting a specific essential enzyme. They’re far better at these jobs than any human-designed substance, Seyedsayamdost says.
To find and catalog new molecules, his lab has developed a way of sorting through the staggering numbers of chemicals microbes can produce. The method, called High-Throughput Elicitor Screening, or HiTES, puts microbial species on lab plates, coaxes them into spitting out their chemical weapons, and quickly analyzes these compounds to figure out their molecular structure and biological activity.
Seyedsayamdost’s HiTES system is already proving effective. It’s found more than a thousand tantalizing compounds, and earned him a MacArthur “genius” grant in 2020.
“Some of these compounds are incredible from a chemical point of view, just structurally speaking,” he says. “Some are more potent and specific than clinically used drugs.”
Others remain more enigmatic, their purpose a mystery. This doesn’t bother Seyedsayamdost. For him, it’s enough that scientists know these molecules exist. He’s recording and cataloging each one in a growing chemical library that is freely available to any researcher who wants to dig deeper.
A few of the compounds his lab has identified offer rays of hope, especially against a drug-resistant microbe called Clostridium difficile. This superpowered bacterium infects the gut, where it can cause violent diarrhea and inflammation of the colon. As its name implies, it can prove nearly ineradicable. Existing antibiotics, which kill off a broad swath of gut bacteria, are powerless against it, and can even make matters worse by clearing away its competitors in the gut.
In 2023, Seyedsayamdost’s lab found a possible solution — a molecule called keratinicyclin B, which is produced by a certain type of soil bacteria. Unlike other antibiotic drugs, it can home in directly on C. diff, attack its cell wall, and wipe out the offending bacteria without causing collateral damage to friendly gut microbes.
Seyedsayamdost, who earned his PhD at MIT, says his interest in making meaningful discoveries began at Brandeis. His faculty mentors — including professor of chemistry and biology Liz Hedstrom; Dan Oprian, the Louis and Bessie Rosenfield Professor of Biochemistry; and former Brandeis biochemistry professor Melissa Moore — introduced him to the world of hands-on research, throwing open the door to the minuscule expanse of biochemistry within every cell.
“I would do my homework in Hedstrom’s lab,” he says. “I would eat there. I would do experiments there. It was a refuge, just such a beautiful world in and of itself.”
Ultimately, Seyedsayamdost wants to move beyond antibiotics and use his methods to find other classes of drugs — like antioxidants; anticancer compounds; and signaling molecules, which let bacteria communicate with one another. Harnessing these latter substances, he notes, may one day allow us to intentionally control how bacteria in our bodies behave, and even mobilize them to kill off pathogens before dangerous infections occur.
As scientists find more and more links between gut bacteria and conditions like inflammatory bowel disease and celiac disease, the idea of treating these disorders at their intestinal source is increasingly attractive.
“Maybe in the future, we won’t have to use antibiotics at all,” Seyedsayamdost says. “Maybe we can figure out how to trigger our own microbiome to produce these antibiotic molecules themselves.”
He savors the thrill of tackling every mystery that comes his way.
“The feeling of discovery is what keeps me going,” he says. “Finding something that in some way rewrites the textbooks, the paradigms, and your own level of understanding — that’s what really drives me.”