Velcro versus bacteria: a new twist in antibiotic warfare

Antibiotic Plectasine

By assembling into large structures, the antibiotic plectasin attaches to its target on the bacterial cell surface. This is similar to how both sides of Velcro form a connection. Credit: Gloria Fuentes, edited

Researchers discovered a new antibacterial mechanism from plectasin, an antibiotic derived from a fungus. The research shows that plectasin forms Velcro-like structures that trap crucial bacterial components, preventing their escape and increasing the drug’s effectiveness. This mechanism could guide the development of new antibiotics to combat antimicrobial resistance.

Plectasin, a small antibiotic, uses an innovative mechanism to kill bacteria. It assembles to form a large structure that snaps onto its target on the bacterial cell surface, similar to how both sides of Velcro form a connection.

A research team mapped out how the Velcro structure is created. Their discovery reveals a new approach that could have broad implications for the development of antibiotics to combat antimicrobial resistance. Published today (May 23) in the scientific journal Natural microbiologyThe research was led by structural biologist Markus Weingarth and biochemist Eefjan Breukink from Utrecht University.

Innovative research techniques

The research team studied the effects of plectasin, an antibiotic derived from the fungus Pseudoplectania nigrella. The scientists 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 in bacterial cells. However, the mechanism behind plectasin’s action has not been fully understood until now. Previous studies suggested a conventional model in which plectasin binds to a molecule called Lipid II, crucial for the synthesis of bacterial cell walls, similar to a key fitting in a lock.

Weingarth group

Maik Derks, Eefjan Breukink, Shehrazade Miranda Jekhmane and Markus Weingarth (from left to right). Credit: Utrecht University

Velcro-like structures with antibacterial effect

The new study reveals a more complicated process. Plectasine not only works like a key in a lock; instead, it forms dense structures on bacterial membranes containing Lipid II. These supramolecular complexes trap their target Lipid II, preventing it from escaping. Even if one Lipid II detaches from plectasin, it remains trapped in the Velcro structure and cannot escape.

Weingarth compares this structure to Velcro, with plectasin forming the microscopic hooks that attach to bacterial ‘loops’. With normal Velcro, if one of the loops comes loose from the hook, it is still attached to the entire structure. The same applies to bacteria trapped in the plectasin superstructure: they can break free from the plectasin binding, but remain trapped in the superstructure. This prevents the bacteria from escaping and causing further infections.

Role of calcium ions in the effectiveness of Plectasine

Furthermore, the researchers found that the presence of calcium ions further enhances the antibacterial activity of plectasin. These ions coordinate with specific plectasin regions and induce structural changes that significantly improve antibacterial effectiveness. That ions play a crucial role in the functioning of plectasin was discovered by PhD students Shehrazade Miranda Jekhmane and Maik Derks, co-first authors of the study. They realized that plectasin samples had a peculiar color, which indicated the presence of ions.

Implications for future antibiotic development

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 candidate for antibiotics due to safety concerns. However, in our study we show that the ‘Velcro mechanism’ appears to be widely used among antibiotics, which has been ignored until now. Future drug design efforts should therefore focus not only on how targets can be bound, but also on how drugs can efficiently self-assemble. Our study therefore closes a major knowledge gap that could have broad implications for the design of better medicines to combat the growing threat of antimicrobial resistance.”

Reference: “Host defense peptide plectasin targets bacterial cell wall precursor lipid II through a calcium-sensitive supramolecular mechanism” by Shehrazade Jekhmane, Maik GN Derks, Sourav Maity, Cornelis J. Slingerland, Kamaleddin HME Tehrani, João Medeiros-Silva, Vicky Charitou, Danique Ammerlaan, Céline Fetz, Naomi A. Consoli, Rachel VK Cochrane, Eilidh J. Matheson, Mick van der Weijde, Barend OW Elenbaas, Francesca Lavore, Ruud Cox, Joseph H. Lorent, Marc Baldus, Markus Künzler, Moreno Lelli, Stephen A. Cochrane, Nathaniel I. Martin, Wouter H. Roos, Eefjan Breukink and Markus Weingarth, May 23, 2024, Natural microbiology.
DOI: 10.1038/s41564-024-01696-9

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