ALTERNATIVE APPROACHES FOR E FAECALIS INFECTIONS

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Enterococci are the 3 most common cause of endocarditis, behind streptococci and staphylococci, and the 2-3 most common cause of hospital acquired infections, with Enterococcusfaecalis being the predominant species isolated. Antimicrobial resistance likely facilitatesthe establishment of enterococci in nosocomial infec- tions and certainly makes it more difficult to successfullytreat patients, particularly those with endocarditis. The central hypothesis of this project is that by better understanding enterococci, new therapeutic or preventative mo- dalities can be developed. Work during a previously funded grant identified and characterized a number of anti- gen encoding genes; a polysaccharide gene cluster (epa) that appears to influencevirulence in mice; different ad- herence phenotypes and a gene, ace, that appears to be involved in adherence; and a gene locus with homology to the accessory gene regulator (agr) locus or staphylococci that is involved in expression of an E. faecalis gelati- nase and a senne protease that also influence virulence in mice. In this application, we propose m to verify that the E.faecalis a^r-like locus regulates gelE and sprE and determine if all are important for virulence;to investi- gate the distribution of these genes among E. faecalis; and to determine how the enterococcal aer-like locus is regulated and if it, like the staphylococcal agr, regulates other genes. We also plan (2) to test the hypothesis that Ace (a newly described adhesm for collagen of enterococci) is the cause of the adherence we haye reported and is important for virulence; to explore the regulation of Ace production; and to determine the distribution and effect of variations in ace, if Ace elicits an antibody response in humans (using recombinantAce and patient sera) in- fected by E.faecalis and if antibody made during infection, or antibody to recombinant Ace, is protective. In our third specific aim, we plan (3) to establish if the polysaccharide gene cluster is the cause of a recently described mucoid phenotype, to study its regulation, and to further test its contribution to adherence to foreign material, virulence and protection. We will also explore a system for constructing non-polar dele^n mutants usingcoun- terselection, based on our prior work with the E.faecalis pyr genes, and to explore additionalassays thatwould help us avoid lethalitymodels. We hope that results from this work will provide solid leads in our quest for meth- ods to prevent, control, or combat E.faecalis infections.