Human β-Defensin 3 Inhibits Cell Wall Biosynthesis in Staphylococci

Sass, V. P.; Schneider, Tanja; Wilmes, Miriam; Körner, Christian; Tossi, Alessandro; Новикова, Н. С.; Shamova, O. V.; Sahl, Hans‐Georg

doi:10.1128/iai.00688-09

Cited by 234 publications

(190 citation statements)

References 47 publications

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“…However, some CAMPs have additional targets that facilitate their toxic effects (40). Particularly well studied are peptides that interact specifically with the peptidoglycan biosynthesis intermediate lipid II at high affinity, including the lantibiotic nisin, fungal defensin plectasin, human neutrophil peptides, and hBD3, allowing them to "dock" at sites of cell-wall synthesis resulting in the sequestration of lipid II away from its functional location and/or resulting in localized membrane pore formation (22,(41)(42)(43)(44)(45). Because nascent PG synthesis, and hence lipid II appearance, occurs in rings emanating from the septal area in ovococci such as E. faecalis, it would not be surprising for lipid II targeting CAMPs to localize to the septal area, as we observe.…”

Section: Discussionmentioning

confidence: 99%

“…Cationic antimicrobial peptides (CAMPs), part of the innate immune repertoire, have a variety of bacterial targets, including anionic membrane constituents such as LPS and teichoic acid, cell-wall precursors, and the phospholipid-rich bacterial cell membrane (20)(21)(22). Accordingly, bacteria have evolved a number of mechanisms to resist CAMP killing (23).…”

Section: Significancementioning

confidence: 99%

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Focal targeting by human β-defensin 2 disrupts localized virulence factor assembly sites in Enterococcus faecalis

Kandaswamy

Liew

Wang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Virulence factor secretion and assembly occurs at spatially restricted foci in some Gram-positive bacteria. Given the essentiality of the general secretion pathway in bacteria and the contribution of virulence factors to disease progression, the foci that coordinate these processes are attractive antimicrobial targets. In this study, we show in Enterococcus faecalis that SecA and Sortase A, required for the attachment of virulence factors to the cell wall, localize to discrete domains near the septum or nascent septal site as the bacteria proceed through the cell cycle. We also demonstrate that cationic human β-defensins interact with E. faecalis at discrete septal foci, and this exposure disrupts sites of localized secretion and sorting. Modification of anionic lipids by multiple peptide resistance factor, a protein that confers antimicrobial peptide resistance by electrostatic repulsion, renders E. faecalis more resistant to killing by defensins and less susceptible to focal targeting by the cationic antimicrobial peptides. These data suggest a paradigm in which focal targeting by antimicrobial peptides is linked to their killing efficiency and to disruption of virulence factor assembly.focal localization | immunofluorescence | microscopy | MprF

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Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Focal targeting by human β-defensin 2 disrupts localized virulence factor assembly sites in Enterococcus faecalis

Kandaswamy

Liew

Wang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition, it is possible that pH might modulate the inhibitory effect of hBD-3 on S. aureus cell-wall biosynthesis. Previous studies found that the bactericidal activity of several defensins involves perturbation of cell-wall biosynthesis by binding to lipid II (67)(68)(69)(70)(71).…”

Section: Discussionmentioning

confidence: 99%

pH modulates the activity and synergism of the airway surface liquid antimicrobials β-defensin-3 and LL-37

Alaiwa¹,

Reznikov²,

Gansemer³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

177

162

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The pulmonary airways are continuously exposed to bacteria. As a first line of defense against infection, the airway surface liquid (ASL) contains a complex mixture of antimicrobial factors that kill inhaled and aspirated bacteria. The composition of ASL is critical for antimicrobial effectiveness. For example, in cystic fibrosis an abnormally acidic ASL inhibits antimicrobial activity. Here, we tested the effect of pH on the activity of an ASL defensin, human β-defensin-3 (hBD-3), and the cathelicidin-related peptide, LL-37. We found that reducing pH from 8.0 to 6.8 reduced the ability of both peptides to kill Staphylococcus aureus. An acidic pH also attenuated LL-37 killing of Pseudomonas aeruginosa. In addition, we discovered synergism between hBD-3 and LL-37 in killing S. aureus. LL-37 and lysozyme were also synergistic. Importantly, an acidic pH reduced the synergistic effects of combinations of ASL antibacterials. These results indicate that an acidic pH reduces the activity of individual ASL antimicrobials, impairs synergism between them, and thus may disrupt an important airway host defense mechanism.

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“…The traditional view holds that electrostatic interactions and disruption of the bacterial membrane cause lethality, which appears to explain the sensitivity of the Gram-negative Escherichia coli (32). However, a recent study failed to find a correlation between ␣-defensin membrane activity and killing of the Gram-positive Staphylococcus aureus, instead attributing cell death to lipid II binding and sequestration (11), a mode of action reminiscent of the lantibiotic peptide nisin (33,34) and other defensins (35)(36)(37). Defensins also neutralize secreted bacterial toxins and virulence factors (1, 38 -42), including anthrax lethal toxin (43)(44)(45), which is a binary complex of two proteins secreted by B. anthracis: lethal factor (LF) 4 and protective antigen (46).…”

mentioning

confidence: 98%

Functional Determinants of Human Enteric α-Defensin HD5

Rajabi

Ericksen

et al. 2012

Journal of Biological Chemistry

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Background: Human ␣-defensin HD5 is a multifunctional antimicrobial peptide whose functional determinants have yet to be elucidated. Results: Alanine scanning mutagenesis aided by x-ray crystallography identified Leu 29 at the dimer interface as crucial; N-methylation of Glu 21 to debilitate HD5 dimerization also affected activity. Conclusion: Dimerization and hydrophobicity are important for HD5 function. Significance: The molecular basis of ␣-defensin function is better understood.

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Human β-Defensin 3 Inhibits Cell Wall Biosynthesis in Staphylococci

Cited by 234 publications

References 47 publications

Focal targeting by human β-defensin 2 disrupts localized virulence factor assembly sites in Enterococcus faecalis

Focal targeting by human β-defensin 2 disrupts localized virulence factor assembly sites in Enterococcus faecalis

pH modulates the activity and synergism of the airway surface liquid antimicrobials β-defensin-3 and LL-37

Functional Determinants of Human Enteric α-Defensin HD5

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