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Proc Natl Acad Sci U S A. 2007 May 29;104(22):9469-74. Epub 2007 May 21.

Gram-positive three-component antimicrobial peptide-sensing system.

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Laboratory of Human Bacterial Pathogenesis and Research and Technology Branch, Research Technologies Section, Genomics Unit, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases/NIH, Hamilton, MT 59840, USA.


To survive during colonization or infection of the human body, microorganisms must circumvent mechanisms of innate host defense. Antimicrobial peptides represent a key component of innate host defense, especially in phagocytes and on epithelial surfaces. However, it is not known how the clinically important group of Gram-positive bacteria sense antimicrobial peptides to coordinate a directed defensive response. By determining the genome-wide gene regulatory response to human beta-defensin 3 in the nosocomial pathogen Staphylococcus epidermidis, we discovered an antimicrobial peptide sensor system that controls major specific resistance mechanisms of Gram-positive bacteria and is unrelated to the Gram-negative PhoP/PhoQ system. It contains a classical two-component signal transducer and an unusual third protein, all of which are indispensable for signal transduction and antimicrobial peptide resistance. Furthermore, our data indicate that a very short, extracellular loop with a high density of negative charges in the sensor protein is responsible for antimicrobial peptide binding and the observed specificity for cationic antimicrobial peptides. Our study shows that Gram-positive bacteria have developed an efficient and unique way of controlling resistance mechanisms to antimicrobial peptides, which may provide a promising target for antimicrobial drug development.

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