James Martin *19: Discovering a Promising Antibiotic

James Martin *19

When he was eight years old, James Martin *19 got a nasty splinter on his hand while climbing a tree with a friend. Thankfully, his mother pulled it out, applied a little antibiotic ointment, and in a few days, his palm had healed.

But Martin is aware that this might not have been the case for a child a century ago, and it might not be so for children born 50 years from now because bacterial resistance to drugs is rising and new antibiotics are incredibly challenging to develop.

Martin’s doctoral thesis offered a shot of hope from a promising antibiotic that performs like a poisoned arrow, attacking malicious bacteria from within and without and felling an adversary as strong as N. gonorrhoeae in mice. Irresistin-16, a derivative of the compound SCH-79797, can simultaneously puncture bacterial walls and disrupt folate metabolism within their cells while not being prone to resistance.

For an antibiotics researcher, this discovery was akin to converting lead to gold, said Martin, who spent most of his graduate career working in the molecular biology lab of Zemer Gitai, the Edwin Grant Conklin Professor of Biology.

Using state-of-the-art methods such as CRISPR screens, proteomics and machine learning, and with the help of colleagues in his lab and other Princeton labs, Martin was able to show that SCH-79797 uses two distinct mechanisms within one molecule, like an arrow coated in poison.

The Florida native first became interested in biology through gardening. As a homeschooled youth, his mother turned chores into lessons and Martin became fascinated with plant life as he grew herbs. He graduated from Florida Atlantic University at age 17 and headed to Princeton to study molecular biology, first with a summer internship, then as a doctoral student.

Now a postdoctoral researcher at the University of Chicago, Martin has turned his attention to understanding cancerous tumors.

What keeps you up at night?

Something that keeps me up at night is how the intellectual community of science is leaning more towards practical application and away from imagination. If I was looking at my doctoral project only in a practical sense, SCH would have never been studied because it was not the most effective of the molecules I was looking at.

Even some of the members on my thesis committee said, “This may be cool, but it may take us years to figure it out, because there’s no standard path [to reverse engineer how the SCH molecule killed bacteria].” But because Zemer was curious, he enabled me to be curious, and we were able to go on this tangential, circuitous, different route. Where we ended up was really exciting.

What inspired you to work in this field in the first place?

Two experiences I had as a child really helped me know that I am very curious. One was, as a kid, I saw a lot of ants walking along the floor. I squished them with my finger. But then I noticed that even if you remove the body, the other ants that came after it started going crazy. It's as if they knew something had happened, even though there was nothing visually for them to see. Years later I found articles talking about the pheromones that are released when ants sense danger and I thought, “That’s really cool.” The second was, I was pulling weeds and noticed that some weeds had little hairs with a few drops of water on them. The water would actually run off. It’s related to the surface tension of the water molecules. I thought this was really interesting, and a question I thought about, that kept me up at night at 10 years old: Why? What advantage would it be to have water that just completely falls off instead of sitting there? Both of those experiences showed me that I was curious about life, how life functions and how it works.

What do you find most exciting now about the work you’re doing?

What’s most exciting to me isn’t learning new things as much now but the opportunity to help others become intellectually mature. Before my postdoc, I was teaching at an urban high school here in Chicago. A real love and a passion I have is helping other people get excited and curious about something. For me, that was science. But I want to give people the opportunity to ground themselves in the fields of interest that they have and ask exciting questions.

How do you hope your work will create a better future?

With regard to the antibiotic work, I hope people open their eyes and realize that we can be imaginative. There is room to be exploratory, especially within the realm of currently known antibiotics.

The big reason we have a problem is that in the past 30 years, we haven’t identified antibiotics with a new mechanism to kill bacteria. In my opinion, humans have been using antibiotics for thousands of years. There are examples where ancient Egyptians would make a poultice out of mud to treat wounds. Interestingly enough, most of our commonly used antibiotics were derived from soil-dwelling bacteria. So why do we have rampant resistance? Well, because we industrialized antibiotics. We made a lot of them, which is great, but we overused them. And the bacteria responded.

I think we need to be creative, be imaginative, but then also be contemporary. We really need to take time to think hard and think deeply about what we’re doing and why we’re doing it — not always looking for the most efficacious bottom line.

I hope my work is a model of doing that. I hope that people see the work that we’ve done and it gives people ideas and makes them curious — that my project is fodder to foster creativity.

What does the term forward thinking mean to you?

For me, personally, I think of 20 years from now, thinking about who is now being inspired to be creative, based on what I’ve done. I hope my forward thinking encourages other young people to do great things, or creates scientific avenues for other people to use my work. If that could happen, then regardless of however other people define successful, I would consider myself to be successful. Forward thinking really means to me, “How can I better help other people be curious?”