Gram-positive three-component antimicrobial peptide-sensing system.
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.
Li
Min
M
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.
Lai
Yuping
Y
Villaruz
Amer E
AE
Cha
David J
DJ
Sturdevant
Daniel E
DE
Otto
Michael
M
D000595:Amino Acid Sequence; D000890:Anti-Infective Agents / Q000494:pharmacology*; D015964:Gene Expression Regulation, Bacterial; D016680:Genome, Bacterial / Q000235:genetics; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D000071677:Histidine Kinase; D006801:Humans; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011494:Protein Kinases / Q000378:metabolism; D012680:Sensitivity and Specificity; D013212:Staphylococcus epidermidis / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D023083:beta-Defensins / Q000494:pharmacology*
D000890:Anti-Infective Agents; D023083:beta-Defensins; D011494:Protein Kinases; D000071677:Histidine Kinase