4 - Cytolethal distending toxins: A paradigm for bacterial cyclostatins

Summary

During the last 10 years, information has accumulated showing that pathogenic bacteria can produce various proteins able to block the eukaryotic cell cycle or delay its progression. These observations raise the attractive hypothesis that control of cell proliferation is a real strategy of pathogenicity, giving an evolutionary advantage to bacteria, and not simply a fortuitous effect observable in cell cultures, the interest of which would eventually be confined to cellular biologists or pharmacologists. The ultimate objective of this chapter is to analyse critically the pertinence of this candidate concept within the field of cellular microbiology (Cossart et al., 1996; Henderson et al., 1998) and to propose tentative criteria to define what we suggest calling bacterial cyclostatins.

We have chosen cytolethal distending toxin (CDT) as a prototype cyclostatin. From a probable common ancestor, CDT has spread through the bacterial world and it can be found in several Gram-negative pathogenic bacteria, constituting a family of toxins sharing common molecular and biological properties in spite of a large genetic dispersion (De Rycke and Oswald, 2001). The presence of a CDT homologue in various unrelated bacterial species is peculiar and suggests that CDT confers a strong selective advantage to producing bacteria, possibly helping adaptation to the host and ecological niche, or increasing pathogenicity. Another major interest in using CDT as a prototype cyclostatin is that a consistent picture of its mode of action on mammalian cells is now emerging, as a result of intensive research effort in recent years by several teams of investigators.