A small antibiotic called plectasin uses a novel mechanism to kill bacteria. By assembling into large structures, plectasin latches onto its target on the surface of the bacterial cell, comparable to how the two sides of Velcro form a bond. A research team, led by structural biologist Markus Weingarth and biochemist Eefjan Breukink at Utrecht University, has mapped how the Velcro structure is formed. Their discovery was published in the scientific journal Nature Microbiologyreveals a new approach that could have broad implications for the development of antibiotics to combat antimicrobial resistance.
The research team studied the function of plectasin, an antibiotic derived from the fungus Pseudoplectania nigrella. The team used advanced biophysical techniques, including solid-state NMR and, in collaboration with Wouter Roos from Groningen, atomic force microscopy.
Traditionally, antibiotics work by targeting specific molecules inside bacterial cells. However, the mechanism behind the action of plectasin was not fully understood until now. Previous studies proposed a conventional model where plectasin binds to a molecule called Lipid II, crucial for bacterial cell wall synthesis, similar to a key fitting a lock.
The new study reveals a more complex process. Plectasin doesn’t just act like a key in a lock. Instead, it forms dense structures in bacterial membranes containing Lipid II. These supramolecular complexes trap their target Lipid II, preventing it from escaping. Even if a Lipid II is released from plectasin, it remains bound to the Velcro structure, unable to escape.
Weingarth compares this structure to Velcro, where plectasin forms the tiny hooks that attach to bacterial “loops.” In regular Velcro, if one of the loops comes off its hook, it is still trapped by the entire construction. The same is true for bacteria trapped in the plectasin superstructure: they can be released from plectasin binding but remain trapped in the superstructure. This prevents bacteria from escaping and causing further infections.
In addition, the researchers found that the presence of calcium ions further enhances the antibacterial activity of plectacin. These ions coordinate with specific regions of plectasin, causing structural changes that greatly improve antibacterial efficacy. That ions play a critical role in plectasin’s action was discovered by PhD students Shehrazade Miranda Jekhmane and Maik Derks, one of the first authors of the study. They realized that the plectasin samples had a strange color, which hinted at the presence of ions.
Markus Weingarth, the study’s lead author, expects that this finding could open new avenues for the development of superior antibiotics. “Plectasin is probably not the ideal antibiotic candidate due to safety concerns. However, in our study, we have shown that the “Velcro mechanism” appears to be widely used among antibiotics, something that has so far been overlooked. Therefore, future drug design efforts should not only focus on how to bind targets, but also how drugs can efficiently self-assemble. Therefore, our study closes an important knowledge gap that could have broad implications for designing better drugs to combat the growing threat of antimicrobial resistance.“
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Journal Reference:
Jekhmane, S., et al. (2024). The host defense peptide, plectasin, targets bacterial cell wall precursor lipid II by a calcium-sensitive supramolecular mechanism. Nature Microbiology. doi.org/10.1038/s41564-024-01696-9.
