In a converted lab in Leiden, researchers have finally caught bacteria in the act—observed at the atomic level exactly how they cheat death when oxygen runs dry. The breakthrough, published in Science Advances, reveals a microscopic sleight of hand: a specialized enzyme called cytochrome bd that keeps bacteria alive and thriving even when oxygen is scarce. For the first time, scientists have not only seen how this enzyme works but discovered how to shut it down—an insight that could reshape the hunt for new antibiotics, including treatments for tuberculosis.
Bacteria are remarkably resourceful. Unlike humans, who depend on steady oxygen to fuel our cells, many bacteria carry a secret trick: when oxygen vanishes, cytochrome bd steps in, allowing them to keep producing the energy they need to survive. This flexibility is precisely what makes certain bacteria so dangerous as pathogens. "Like us, these bacteria need oxygen to survive," explains Ph.D. candidate Tijn van der Velden. "But unlike humans, they have a special enzyme called cytochrome bd that allows them to keep producing energy even when oxygen levels are very low." The enzyme's critical role in bacterial survival makes it an obvious target for new drugs—but only if researchers can understand exactly how it works.
For years, that understanding remained frustratingly out of reach. The key part of cytochrome bd is constantly flexing and moving, making it nearly impossible to study under a microscope. "We needed to find a way to stabilize it," Van der Velden explains. The breakthrough came not from a new theory but from a new tool: the Glacios microscope, which allowed the team to examine the enzyme at atomic resolution. Even more crucial, however, was the freedom that came with it. Unlike the overbooked Krios microscope used previously, the Glacios gave researchers the chance to repeat experiments and refine their methods step by step.
The key insight emerged from an unlikely source: a gentler detergent. Chemists normally use strong chemicals to extract enzymes from a bacterium's fatty cell membrane—a necessary step before study. But the Leiden team tried a milder alternative, and it changed everything. "With this detergent, the enzymes came out as dimers: pairs of identical proteins that remain attached to each other," Van der Velden says. Those paired proteins were far more stable and less mobile than the single, mangled proteins produced by harsh detergents, finally revealing the enzyme's flexible moving parts.
The team then watched something unusual unfold: they applied a known inhibitor—a chemical that normally just blocks an enzyme's binding site—and discovered it did far more. "The inhibitor does more than just block the binding site—it actually changes the shape of the enzyme," Van der Velden says. The compound forces the enzyme to fold differently, squeezing shut the very area where energy production happens. It's an uncommon mechanism, yet it offered researchers a clear window into how these enzymes can be disabled.
The inhibitor itself cannot become medicine. As Lars Jeuken, Van der Velden's supervisor, notes: "The compound is also harmful to human cells. It kills bacteria, but unfortunately it is also lethal to humans." But that limitation is temporary. "For the first time, we have been able to see at an atomic scale what happens inside this type of protein, how it provides bacteria with the energy they need to survive, and how the process can be blocked," Van der Velden says. Other researchers can now use this structural insight to design new inhibitors—compounds that exploit the same refolding mechanism but spare human cells. Gradually, step by deliberate step, the path to selective antibiotics becomes clearer.