Antibacterial peptides are found across the animal kingdom, serving roles in nature by fighting microbial infections and diseases such as cancer. Now researchers at the Technion-Israel Institute of Technology and the European Molecular Biology Laboratory in Hamburg, report they have discovered the molecular properties of an antibacterial peptide, uperin 3.5, that is secreted on the skin of the Australian toadlet. Their findings may lead to the development of new synthetic drugs to combat bacterial infections.

Their study, “The amphibian antimicrobial peptide uperin 3.5 is a cross-α/cross-β chameleon functional amyloid,” is published in the journal Proceedings of the National Academy of Sciences.

The researchers discovered that the peptide uperin 3.5 self-assembles into a unique fibrous structure, that can change its form in the presence of bacteria to protect the toadlet from infections.

The peptide uperin 3.5 is secreted by the Australian toadlet’s skin. When exposed to bacterial membranes, it rapidly changes its structure and transforms into a deadly antimicrobial weapon. These pictures were taken using a transmission electron microscope (TEM) in the Electron Microscopy Centers in the Technion department of materials science and engineering and in the department of chemical engineering. The cross-α atomic structure was determined by data collected at the ESRF synchrotron.[Nir Salinas/Technion]
“Antimicrobial activity is being increasingly linked to amyloid fibril formation, suggesting physiological roles for some human amyloids, which have historically been viewed as strictly pathological agents,” the investigators wrote. “This work reports on formation of functional cross-α amyloid fibrils of the amphibian antimicrobial peptide uperin 3.5 at atomic resolution, an architecture initially discovered in the bacterial PSMα3 cytotoxin.”

The researchers observed that the antibacterial fibrils on the toadlet’s skin have a structure that resembles amyloid fibrils, which are a hallmark of neurodegenerative diseases.

This finding may provide insights into potential physiological properties of amyloid fibrils associated with neurodegenerative and systemic disorders.

“The fibrils of uperin 3.5 and PSMα3 comprised antiparallel and parallel helical sheets, respectively, recapitulating properties of β-sheets. Uperin 3.5 demonstrated chameleon properties of a secondary structure switch, forming mostly cross-β fibrils in the absence of lipids. Uperin 3.5 helical fibril formation was largely induced by, and formed on, bacterial cells or membrane mimetics, and led to membrane damage and cell death. These findings suggest a regulation mechanism, which includes storage of inactive peptides as well as environmentally induced activation of uperin 3.5, via chameleon cross-α/β amyloid fibrils.”

When the peptide encounters the bacterial membrane, it changes its molecular configuration to a less compact cross-α form. “This is a sophisticated protective mechanism of the toadlet, induced by the attacking bacteria themselves,” explained Meytal Landau, PhD, structural biologist, Technion-Israel Institute of Technology and lead author of the study. “This is a unique example of an evolutionary design of switchable supramolecular structures to control activity.”

The researchers hope that their findings will lead to the development of novel synthetic drugs to combat bacterial infections that would be activated only in the presence of bacteria.

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