Clostridium sordellii causes lethal infections in humans and animals, characterized by an extreme increase in circulating leukocytes deemed the leukemoid reaction (LR). C. sordellii produces several virulence factors, only neuraminidase is known to be implicated in the induction of the extreme LR. In the present study we identify a previously unknown extracelllular metalloproteinase (MCs1) in C. sordellii ATCC 9714. Supernatants generated from expression vector containing rMCs1 exhibit cleavage activity against VCAM-1 and CRCX4 whereas supernatants generated from the mutant strain were devoid of cleavage activity. We further characterize the structure and functions of MCs1 at a molecular level using a combination of bioinformatic and structural biology methods. A 3D homology model is constructed and followed by a molecular dynamics simulation to obtain the optimized MCs1 structure. The putative interacting amino acid sequences and binding interfaces on MCs1 and VCAM-1/CXCR4 are located. Protein-protein docking of MCS1 and its binding partners is performed to provide molecular insights into MCs1's cleavage activity. This study represents the first molecular identification and characterization of an important proteinase produced by a clostridial species that directly induces LR. We expect that MCs1 will be a promising drug target and our results will open a new door to novel antibiotic discovery against C. sordellii.

Molecular identification and characterization of a novel extracellular metalloproteinase produced by Clostridium sordellii

251st National Meeting (2016)

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