Our laboratory focuses on developing new ways to prevent and treat antibiotic resistant infections. We believe the core genome of enterococci and staphylococci evolved to enable stable commensal relationship with the host. However, this stability is undermined by environmental changes, changes in the host, or the introduction into the microbe of new traits on mobile elements. We identify traits on mobile elements that destabilize the host commensal relationship, determine their origin, and define how they undermine the balance. These studies employ epidemiology, molecular genetics and genomics, cell biology and pathogenesis in animal models.
We were part of the team that described the first vancomycin-resistant Enterococcus isolated in the US, which led us to discover a capsule locus and a pathogenicity island among hospital ward endemic strains. The pathogenicity island harbors over 120 genes, including a new adhesin that contributes to biofilm formation, and a novel cytolysin toxin. We showed that the post-translationally modified cytolysin is regulated by a novel system that permits the microbe to sense target cells. To study their subtle pathogenesis, we developed several novel infection and colonization models. We defined the microbiome of Drosophila, which includes enterococci as a native member. We also developed a highly tractable model for studying the pathogenesis of enterococcal and staphylococcal infection in mice, utilizing the vitreous chamber. Because the medium is clear and visible, it permits direct, real time examination of the infection. This allowed us to show that in the absence of cytolysin expression, E. faecalis infection resulted in substantial inflammation but no direct tissue damage, and could be successfully treated. However, if the strain expressed cytolysin, no therapeutic regimen mitigated the course. Similar types of analysis have been made for staphylococci.
Because microorganisms in biofilms are highly resistant to antibiotic killing, we also have investigated the molecular biology of biofilm formation by gram positive cocci. We developed a protracted biofilm model that examined gene expression over the course of 30 days. This study led us to observe that there is a dramatic bacterial population crash after about 1 week in this model, followed by the outgrowth of very stable architectural structures that supported increased numbers of bacteria for the duration of the study. These observations led us to propose a new model for biofilm formation by gram positive cocci that involves programmed fratricide and the incorporation of released DNA into the biofilm structure.
Recently we have worked with the Broad Institute to characterize the enterococcci at the genomic level, and announced the release of 28 new enterococcal genome sequences. To promote research nationally and internationally into these leading causes of resistant infection, we launched the International ASM Conference on Enterococci series, organized the main textbook on the subject (Gilmore MS. 2002. The Enterococci: Pathogenesis, Molecular Biology, and Antibiotic Resistance. Washington, DC: ASM Press.), have organized international conferences on streptococcal genetics and functional genomics, and promote these areas on national and international committees.
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