The non‐enzymatic microbicidal activity of lysozymes

Düring, Klaus; Porsch, Petra; Mahn, Andreas; Brinkmann, Olaf; Gieffers, W.

doi:10.1016/s0014-5793(99)00405-6

Cited by 251 publications

(187 citation statements)

References 22 publications

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“…Synergistic effects may occur when one peptide in a conformation parallel to the bacterial membrane facilitates insertion of other peptides (63). We speculate that such an effect might account for synergistic activity between hBD-3 and LL-37 as well as synergism for the combination of LL-37 and lysozyme; in addition to its enzymatic activity, lysozyme has nonenzymatic antibacterial activity dependent on its cationic and hydrophobic domains that disrupt bacterial plasma membranes (64)(65)(66). A possibility that we cannot exclude is that variations in pH might render S. aureus and P. aeruginosa more or less susceptible to antimicrobial factors.…”

Section: Discussionmentioning

confidence: 96%

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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Section: Discussionmentioning

confidence: 96%

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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“…On the other hand, the activity of the CfP1 phage seems to tolerate higher pH values better than the recombinant lysin, which indicates that other lytic accessory proteins might have an important role in phage antibacterial activity. The ability of a Gram-negative-specific phage lysin to kill cells Bfrom without^has been solely attributed to few enzymes (e.g., Enterobacter phage T4, Bacillus phage PlyL, Acinetobacter phage PlyF307, and Pseudmonas phage OBP lysins) (During et al 1999;Morita et al 2001;Walmagh et al 2012;Lood et al 2015). This effect was associated to the positively charged amino acids located at the enzyme's Ctermini, which is able to disrupt or mediate lysin access to the peptidoglycan, causing subsequent bacteriolysis.…”

Section: Discussionmentioning

confidence: 99%

Characterization and genome sequencing of a Citrobacter freundii phage CfP1 harboring a lysin active against multidrug-resistant isolates

Oliveira

Pinto

Oliveira

et al. 2016

Appl Microbiol Biotechnol

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Citrobacter spp., although frequently ignored, is emerging as an important nosocomial bacterium able to cause various superficial and systemic life-threatening infections. Considered to be hard-to-treat bacterium due to its pattern of high antibiotic resistance, it is important to develop effective measures for early and efficient therapy. In this study, the first myovirus (vB_CfrM_CfP1) lytic for Citrobacter freundii was microbiologically and genomically characterized. Its morphology, activity spectrum, burst size, and biophysical stability spectrum were determined. CfP1 specifically infects C. freundii, has broad host range (>85 %; 21 strains tested), a burst size of 45 PFU/cell, and is very stable under different temperatures (−20 to 50°C) and pH (3 to 11) values. CfP1 demonstrated to be highly virulent against multidrug-resistant clinical isolates up to 12 antibiotics, including penicillins, cephalosporins, carbapenems, and fluroquinoles. Genomically, CfP1 has a dsDNA molecule with 180,219 bp with average GC content of 43.1 % and codes for 273 CDSs. The genome architecture is organized into function-specific gene clusters typical for tailed phages, sharing 46 to 94 % nucleotide identity to other Citrobacter phages. The lysin gene encoding a predicted D-Ala-D-Ala carboxypeptidase was also cloned and expressed in Escherichia coli and its activity evaluated in terms of pH, ionic strength, and temperature. The lysine optimum activity was reached at 20 mM HEPES, pH 7 at 37°C, and was able to significantly reduce all C. freundii (>2 logs) as well as Citrobacter koseri (>4 logs) strains tested. Interestingly, the antimicrobial activity of this enzyme was performed without the need of pretreatment with outer membrane-destabilizing agents. These results indicate that CfP1 lysin is a good candidate to control problematic Citrobacter infections, for which current antibiotics are no longer effective.

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“…Although the concept of muramidase-independent killing of bacteria continues to be debated (27), there is increasing evidence in support of this hypothesis (20,22,28,29). Recent studies identified a bactericidal domain that mapped to the C-terminal region of chicken and human lysozyme (30).…”

Section: Lysmmentioning

confidence: 99%

The Peptidoglycan-Degrading Property of Lysozyme Is Not Required for Bactericidal Activity In Vivo

Nash

Ballard

Weaver

et al. 2006

The Journal of Immunology

134

113

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Lysozyme is an abundant, cationic antimicrobial protein that plays an important role in pulmonary host defense. Increased concentration of lysozyme in the airspaces of transgenic mice enhanced bacterial killing whereas lysozyme deficiency resulted in increased bacterial burden and morbidity. Lysozyme degrades peptidoglycan in the bacterial cell wall leading to rapid killing of Gram-positive organisms; however, this mechanism cannot account for the protective effect of lysozyme against Gram-negative bacteria. The current study was therefore designed to test the hypothesis that the catalytic activity (muramidase activity) of lysozyme is not required for bacterial killing in vivo. Substitution of serine for aspartic acid at position 53 (D53S) in mouse lysozyme M completely ablated muramidase activity. Muramidase-deficient recombinant lysozyme (LysMD53S) killed both Gram-positive and Gram-negative bacteria in vitro. Targeted expression of LysMD53S in the respiratory epithelium of wild-type (LysM+/+/LysMD53S) or lysozyme Mnull mice (LysM−/−/LysMD53S) resulted in significantly elevated lysozyme protein in the airspaces without any increase in muramidase activity. Intratracheal challenge of transgenic mice with Gram-positive or Gram-negative bacteria resulted in a significant increase in bacterial burden in LysM−/− mice that was completely reversed by targeted expression of LysMD53S. These results indicate that the muramidase activity of lysozyme is not required for bacterial killing in vitro or in vivo.

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The non‐enzymatic microbicidal activity of lysozymes

Cited by 251 publications

References 22 publications

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

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

Characterization and genome sequencing of a Citrobacter freundii phage CfP1 harboring a lysin active against multidrug-resistant isolates

The Peptidoglycan-Degrading Property of Lysozyme Is Not Required for Bactericidal Activity In Vivo

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