The Role of Enterococcus Unique Hypothetical EF1909 in Intrinsic β-lactam Resistance

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Project summary: Enterococci are leading causes of multidrug resistant hospital acquired infection – the first E in the ESKAPE acronym. We recently showed that the genus Enterococcus differs from its closest extant ancestors in having evolved enhanced traits for survival, including to starvation and desiccation, as well as to challenge by antibiotics and other biocides that target the cell surface. That is, in diverging from its ancestors hundreds of millions of years ago, it gained features making the cell more rugged and impermeable. We found that enterococci possess 10 genes that are rare or do not exist outside of the genus. Moreover, we found that one of these, encoding a hypothetical protein, contributes to intrinsic resistance to b-lactams – the largest class of antibiotics used in human medicine. As a result of this intrinsic resistance, this antibiotic class has been of limited use in controlling enterococcal infection. Here we propose to validate the preliminary results implicating this gene, termed EF1909, in contributing to intrinsic b-lactam resistance and more rigorously and fully assess the phenotype of cells engineered to lack this feature. We additionally assess when in the growth cycle that EF1909 is expressed and determine whether its presence/absence results in cell wall peptiglycan of altered composition as implicated by its contribution to intrinsic b-lactam resistance. If we are able to substantiate the preliminary indications of phenotype in this exploratory work, this would raise the prospect of then screening for EF1909 inhibitors that would be predicted to render enterococci now vulnerable to inexpensive and readily available b-lactam antibiotics. Rendering enterococci readily treatable by b-lactams would be an advance of very high impact for global health.