Multiple-Drug Resistant Enterococci: The Nature of the Problem and an Agenda for the Future
Mark M. Huycke*†, Daniel F. Sahm‡, and Michael S. Gilmore†
Author affiliations: *University of Oklahoma Health Sciences Center, Oklahoma, USA; †Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma, USA; ‡MLR Pharmaceutical Services, Inc., Reston, Virginia, USA
Figure 4. Cytolysin is expressed and processed through a complex maturation pathway (64). The cytolysin precursors, CylLL and CylLS, are ribosomally synthesized. The putative modification protein, CylM, is required for the expression of CylLL and CylLS in an activatable form, and the secreted forms, CylLL and CylLS were recently shown to possess the amino acid lanthionine as the result of posttranslational modification (64). CylLL and CylLS both are secreted by CylB (65), which is accompanied by an initial proteolytic trimming event (64) converting each to CylLL' and CylLS', respectively. Once secreted, CylLL' and CylLS' are both functionally inactive until six amino acids are removed from each amino terminus. This final step in maturation is catalyzed by CylA (64), a subtilisin-type serine protease. Since this final catalytic event is essential, occurs extracellularly, and is catalyzed by a class of enzyme for which a substantial body of structural information exists, it represents an ideal therapeutic target. As shown in Figure 3, inhibition of cytolysin by mutation (or potentially by therapeutic intervention) results in a reduction by several orders of magnitude in the number of circulating organisms.
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