But all that could change, thanks to groundbreaking findings to be published tomorrow in Science by a
The researchers discovered ‘ammunition’ that assists the infectious bacterium: a novel form of an amyloid fibril whose
One of the
The «Mad Cow» prion, like all amyloids discovered so far, belongs to a group possessing what is called a cross-ß structure. In the present study, an amyloid of a completely new structure was discovered, which was named cross-α.
«At some point we knew that we had found something unique, but only after several trips to cyclic particle accelerators (Synchrotrons) in Grenoble and Chicago were we successful in verifying its being a new type of amyloid," said Prof. Landau. «Much more work was required before we could publish our findings, but from the very first moment, it was clear to us that what we had was a paradigm shift.»
Crystal structures of disease-associated human amyloid fibril (right) and novel bacterial amyloid fibril (left). Three-dimensional structures of the fibrils were obtained using x-ray microcrystallography – a method that provides information at the single-atom level. The image depicts the long fibrils, which can theoretically be extended on both sides. The fibril is composed of two adjacent “surfaces” (purple and gray), called sheets, which mate via strong chemical interactions. Each sheet is built from self-association of peptides, horizontally running along the sheet. While the overall shape of mating sheets is similar among the human and bacterial fibrils, the basic units of the fibril (individual peptides) assume a completely different form. In the canonical amyloid structure observed in human diseases (right), the peptides form extended ribbons (called beta-strands). In the novel bacterial fibril (left), the peptides are spiral like telephone cords (called alpha-helices). Thus, if until today amyloids were defined as cross-beta structures (the beta-strands are perpendicular to the mating sheets, hence the crossing referral), the new structure shows that a cross-alpha fibrils can also exist (with alpha-helices stack perpendicular to the vertical axis of the fiber). This extends the repertoire of the amyloid phenomenon.
She estimates that the new discovery will lead to the development of antibiotics with a new action mechanism. Such drugs will inhibit the amyloid formation thereby neutralizing one of the important ‘weapons’ in the arsenal of this pathogenic bacterium. In her opinion, since this antibiotic is not aimed at killing the bacterium but only reducing its toxicity to humans, it will not lead to a rapid development of bacterial resistance towards it.
«Resistance to antibiotics develops in bacteria due to evolutionary pressure — natural selection leads to the growth of bacteria which antibiotics are unable to kill," she said. «If we reduce the pressure on the bacterium and don’t kill it but rather prevent its pathogenic aspects, the resistance will probably not rush to develop.»
Looking towards the future, Prof. Landau clarifies that «in academia itself, it’s difficult to carry out a full process of drug development due to the prohibitive cost entailed. Nevertheless, we can provide drug developers with scientific knowledge that will accelerate and lower the costs of the process. The present discovery is a
«From the scientific standpoint, there is an important lesson here — thinking out of the box opens new doors," she continued. «In this specific case, extending the repertoire of amyloids. Deciphering new structures of amyloids might lead to new insights regarding mechanisms of neurodegenerative diseases. It might also lead to the discovery of ‘good’ amyloids that take part in an organism’s natural protection against infections. Such research could lead to the development of novel means of protection against the toxins found in bacteria and fungi.»
The research was conducted by members of the Landau lab, including Einav