Enterococci are opportunistic pathogens that can cause severe bacterial infections. Treatment of these infections is challenging because enterococci possess intrinsic and acquired resistance to commonly used antibiotics.
Enterococcus faecalis is a Gram-positive
bacterium that is a major cause of hospital-acquired infections due,
in part, to its intrinsic resistance to cell wall-active antimicrobials.
One critical determinant of this resistance is the transmembrane kinase
IreK, which belongs to the penicillin-binding protein and serine/threonine
kinase-associated kinase family of bacterial signaling proteins involved
with the regulation of cell wall homeostasis. The activity of IreK
is enhanced in response to cell wall stress, but direct substrates
of IreK phosphorylation, leading to antimicrobial resistance, are
largely unknown. To better understand stress-modulated phosphorylation
events contributing to antimicrobial resistance, wild type E. faecalis cells treated with cell wall-active antimicrobials,
chlorhexidine or ceftriaxone, were examined via phosphoproteomics.
Among the most prominent changes was increased phosphorylation of
divisome components after both treatments, suggesting that E. faecalis modulates cell division in response to
cell wall stress. Phosphorylation mediated by IreK was then determined
via a similar analysis with a E. faecalis ΔireK mutant strain, revealing potential
IreK substrates involved with the regulation of peptidoglycan biosynthesis
and within the E. faecalis CroS/R two-component
system, another signal transduction pathway that promotes antimicrobial
resistance. These results reveal critical insights into the biological
functions of IreK.
Enterococci are Gram-positive, opportunistic pathogens and inhabitants of the gastrointestinal tract of most terrestrial organisms. Enterococci are considered to be commensals, but in immunocompromised or debilitated individuals, they can cause deadly infections
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