A Chemical Biology student is developing a multipronged therapy to tackle drug-resistant bacteria

John P. Santa Maria, Jr., a fourth-year PhD student in chemical biology, talks a lot about solving difficult problems. At the moment, the foremost on his mind is a 180-mile race he plans to run along the length of Cape Cod, from Plymouth to Provincetown. His secret weapon, in this case, is the “Fanny Pack,” his relay team of eight, each clad in a different color of the rainbow and each, of course, wearing fanny packs.

His academic work, while perhaps not as colorful, is every bit as difficult: as a researcher in the Walker Lab, he focuses on thwarting antibiotic resistance in Staphylococcus, the bacteria responsible for Staph infections. And like his relay team, the approaches Santa Maria is developing are based on the principle that more is better.

“What we want to do is deliver a one-two punch,” he explains. “So that if the bacteria develops a resistance to the first attack, there’s a second attack waiting for it.” Since the earliest days of antibiotics, the problem of bacterial resistance has proved an obstinate one. Because bacteria exist in such great numbers and reproduce so quickly, evolution is on their side: every new bacterium is a new chance to win the genetic lottery and produce just the mutation that will allow it and its descendants to survive a given antibiotic. The aim of the “combination therapy” under development by researchers like Santa Maria is to “cut the bacteria off at all passes” by anticipating potential mutations and incorporating as many responses to them as possible in one drug.

The same versatility that Santa Maria hopes to cultivate in antibiotics has also characterized his career at Harvard. His original dissertation project was on tunicamycin, a naturally produced compound that knocks out Staph’s resistance to drugs like penicillin. While presenting his work at a conference in Croatia the summer after his second year, he was approached by a research team from England. “They just wanted to let me know that they had solved the problem I was investigating and were about to publish on it,” he recalls. “At first I was scared – where could I go from there? But I also felt sort of vindicated, because their solution was pretty close to the one I had been working on.” Now, Santa Maria is glad he was scooped, since it forced him to turn to more complex problems. While his original project aimed only to identify the membrane polymer that tunicamycin was disabling, he is now exploring exactly why Staph depends on that polymer, and how disabling it leaves the bacteria vulnerable to subsequent attack.

Given the multipronged approach Santa Maria takes to deadly microbes, it’s easy to understand what appeals to him about chemical biology. “We can go near the chemistry that the biologists are afraid of, and near the biology that the chemists are afraid of,” he explains, adding that “Suzanne Walker’s lab has provided me with the tools this requires, as well as a conducive learning environment.” As an undergraduate chemistry major at Muhlenberg College in Pennsylvania, Santa Maria happened to see Walker give a talk on efforts to synthetically improve existing antibiotics. It was all he needed to decide what he wanted to do in graduate school. “Given the fluidity of biology, any one approach is just going to be too limiting. Chemical biology is all about coordinating approaches.”

The more time Santa Maria spends at Harvard, the more he appreciates how the University’s resources allow for such coordination — one of the aims of the Harvard Integrated Life Sciences Program. “It really is a privilege to be around so many smart people and amazing opportunities,” he says, “and the longer I’m here, the more I try to exploit that. We can do things here that you just can’t do at most other places.”

For Santa Maria, those things will soon include running across Cape Cod in a red fanny pack. And thanks to the complex tools of chemical biology, they may one day include developing powerful new approaches to the seemingly insoluble problem of antibiotic resistance. — Nicholas Nardini