At Leiden University in the Netherlands, Ph.D. candidate Vladyslav Lysenko faced a humbling realization: the tuberculosis antibiotic evybactin, a promising compound discovered by researchers in Boston, simply didn't work when he first synthesized it. A single tiny error in the molecule's proposed structure had obliterated all its activity—a stark reminder that drug design operates at the threshold where nanoscopic precision determines life-saving efficacy or complete failure.
The global antibiotic resistance crisis demands solutions from multiple fronts. As bacteria evolve defenses against our most powerful medicines, researchers must simultaneously hunt for entirely new weapons and maximize the effectiveness of the ones we already have. Lysenko's work exemplifies the first approach: diving into the smallest molecular details to revive and improve antibiotic candidates that initially seemed doomed.
What makes evybactin compelling is its potential against Mycobacterium tuberculosis, the bacterium responsible for tuberculosis—a disease that still kills more than a million people globally each year. When Lysenko and his team corrected that single structural error, the molecule came alive. By systematically redesigning and improving the compound, they didn't just rescue an abandoned candidate; they secured two patents and kept evybactin alive as a focus of Prof. Nathaniel Martin's ongoing research group at Leiden.
The work reflects a broader philosophy that animates the lab's approach: learning from nature's own pharmaceutical arsenal. Bacteria have been waging chemical warfare against each other for millions of years, producing substances specifically designed to kill competitors. Modern antibiotics are built on this foundation. By studying these natural weapons and replicating them in the laboratory, researchers can adapt and refine them—making them more stable, more effective, reducing side effects—so they perform better in the human body.
But even as Lysenko pursues new molecules, his colleague Sebastian Tandar attacks antibiotic resistance from a different angle. While Lysenko works at the chemical level, Tandar asks how existing antibiotics actually behave inside real patients. Rather than waiting for new drugs to arrive—a process that takes years or decades—his research aims to extend the lifespan of the antibiotics we have now, buying time while scientists develop replacements. In collaboration with Coen van Hasselt's research group, Tandar uses mathematical modeling to translate laboratory findings into clinical reality, simulating how different drug combinations might work in patients.
One of Tandar's key discoveries involves collateral sensitivity: the phenomenon where bacteria that develop resistance to one drug become more vulnerable to another. By identifying reliable drug combinations that trigger this effect, testing them experimentally, and building models to predict patient outcomes, his team has uncovered strategies that could prevent resistance from spreading quite so quickly. This concept—using the bacteria's own evolutionary adaptations against it—represents a subtle but potentially powerful way to extend the usefulness of current treatments.
Both researchers defended their doctoral theses in May: Lysenko on the 21st and Tandar cum laude on the 27th. Their divergent paths toward the same goal reflect an emerging consensus in the fight against antibiotic resistance: we need new drugs, yes, but we also need smarter ways to use the ones we have. The challenge is urgent and multifaceted. As Tandar notes, the window is narrowing—once new antibiotics are introduced, strategies must be in place to prevent resistance from emerging quickly, or new discoveries will rapidly lose their impact. At Leiden University, researchers are working to ensure that window stays open.