HMN 2026: How Tiny molecular fix revived tuberculosis antibiotic candidate and led to two patents

How can we combat the growing global health crisis of antibiotic resistance? At Leiden University, researchers are tackling this issue from multiple angles. Ph.D. candidate Vladyslav Lysenko develops and redesigns new antibiotic molecules, while Sebastian Tandar studies how existing antibiotics can be used more effectively.

Bacteria have been fighting each other for millions of years. In that battle, they have developed substances that kill their competitors. “We can learn from that,” says Ph.D. candidate Lysenko. In Leiden, he is investigating how such natural weapons can be developed into new antibiotics. He defended his doctoral thesis on May 21.

Learning from bacteria themselves

In the lab, Lysenko is searching for solutions at the smallest level: molecules. He focuses on so-called “natural” antibiotics—substances that microorganisms produce themselves to compete with other bacteria in their environment. Many of the antibiotics used today are based on these kinds of substances.

By replicating them in the lab, researchers can better understand and adapt them so they work more effectively in the human body, for example by making them more stable or reducing side effects.

Small change, big effect

His Ph.D. covered the full process, from discovery to redesign. One example is evybactin, a promising compound discovered by the lab of Kim Lewis in Boston that showed potent activity against Mycobacterium tuberculosis, the bacterium that causes tuberculosis.

When Lysenko first synthesized the evybactin molecule, it showed no activity. The team later found that a small error in the originally proposed structure led to a complete loss of activity, underscoring how sensitive drug design can be. Tiny chemical changes determine whether a drug works or fails.

After correcting it, they were able to redesign and improve the compound, leading to two patents. Evybactin remains an important focus of ongoing research in the group of Prof. Nathaniel Martin.

Getting more out of what we already have

While Lysenko worked at the molecular level, Tandar approached the same problem from a different perspective: how antibiotics behave in real patients. “Our goal is to make better use of the antibiotics we already have, to stay ahead of antibiotic resistance.”

In the research group of Coen van Hasselt, Tandar combined laboratory and clinical data through mathematical modeling, simulating how treatments would behave in the body.

“These models can help translate results from the lab to the clinic,” Tandar says.

He defended his doctoral thesis cum laude on May 27.

Buying time while developing new drugs

One of the key concepts he studied is collateral sensitivity, in which resistance to one drug increases sensitivity to another.

“We identified drug combinations that could reliably produce this effect, tested them experimentally, and built mathematical models to simulate how such treatments might work in patients.”

If such strategies can be translated into clinical practice, they could extend the lifespan of existing antibiotics—buying valuable time while new drugs are developed.

Two approaches, one goal

Although their approaches differ, both researchers are working toward the same goal: keeping antibiotics effective for the future.

While many straightforward discoveries have already been made, new technologies and access to previously unculturable bacteria offer new opportunities. Lysenko remains optimistic: “We continue to discover natural products that were previously inaccessible to us.”

“We need both approaches,” Tandar says. “If bacteria become resistant to all existing antibiotics, we need new ones. But developing new drugs takes time. In the meantime, we can extend the usefulness of current antibiotics. And once new antibiotics are introduced, we need strategies to prevent resistance from emerging quickly, or new discoveries will quickly lose their impact.”

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