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Crystal Structures Define Mode of Action of Bacteriophage Endolysins

By BiotechDaily International staff writers
Posted on 13 Aug 2014
Image: Electron microscopy image of the bacteriophages investigated (Photo courtesy of the European Molecular Biology Laboratory).
Image: Electron microscopy image of the bacteriophages investigated (Photo courtesy of the European Molecular Biology Laboratory).
Image: The analyzed endolysins are activated by switching from a tensed, stretched state (left) to a relaxed state (right) (Photo courtesy of the European Molecular Biology Laboratory).
Image: The analyzed endolysins are activated by switching from a tensed, stretched state (left) to a relaxed state (right) (Photo courtesy of the European Molecular Biology Laboratory).
New antibacterial agents based on bacteriophages or their endolysin enzymes have been proposed to solve the problem of the bacterium Clostridium difficile, which is becoming a serious health hazard in hospitals and healthcare institutes, due to its resistance to antibiotics.

Investigators at the European Molecular Biology Laboratory (Hamburg, Germany) based their research primarily on the bacteriophage CD27, which is capable of lysing C. difficile. In addition, they worked with a recombinant form of the CD27L endolysin, which lyses C. difficile in vitro.

To better understand how the lysis process works, the investigators determined the three-dimensional structures of the CD27L endolysin and the CTP1L endolysin from the closely related bacteriophage CPT1 that targets C. tyrobutyricum. For this task they employed X-ray crystallography and small angle X-ray scattering (SAXS), which was done at the Deutsches Elektronen-Synchrotron (DESY).

Results published in the July 24, 2014, online edition of the journal PLOS Pathogens revealed that the two endolysins shared a common activation mechanism, despite having been taken from different species of Clostridium. The activation mechanism depended on a structure where an extended dimer existed in the inactive state but switched to a side-by-side "relaxed" morphology in the active state, which triggered the cleavage of the C-terminal domain. This change of morphology led to the release of the catalytic portion of the endolysin, enabling the efficient digestion of the bacterial cell wall.

“These enzymes appear to switch from a tense, elongated shape, where a pair of endolysins is joined together, to a relaxed state where the two endolysins lie side-by-side,” said first author Dr. Matthew Dunne, a researcher at the European Molecular Biology Laboratory. “The switch from one conformation to the other releases the active enzyme, which then begins to degrade the cell wall.”

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