In vitro assessment of antimicrobial peptides as potential agents against several oral bacteria

Altman, Hamutal; Steinberg, Doron; Porat, Yaara; Mor, Amram; Fridman, Diego; Friedman, Michael; Bachrach, Gilad

doi:10.1093/jac/dkl181

Cited by 114 publications

(90 citation statements)

References 10 publications

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“…actinomycetemcomitans is resistant to LL-37. As previously observed (24), A. actinomycetemcomitans treated with LL-37 at physiological ionic strength maintained growth at all tested LL-37 concentrations (up to 100 g/ml) (Fig. 1A).…”

Section: Resultssupporting

confidence: 87%

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LL-37 Opsonizes and Inhibits Biofilm Formation of Aggregatibacter actinomycetemcomitans at Subbactericidal Concentrations

et al. 2013

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Host defense peptides are immediate responders of the innate immunity that express antimicrobial, immunoregulatory, and wound-healing activities. Neutrophils are a major source for oral host defense peptides, and phagocytosis by neutrophils is a major mechanism for bacterial clearance in the gingival tissue. Dysfunction of or reduction in the numbers of neutrophils or deficiency in the LL-37 host defense peptide was each previously linked with proliferation of oral Aggregatibacter actinomycetemcomitans which resulted in an aggressive periodontal disease. Surprisingly, A. actinomycetemcomitans shows resistance to high concentrations of LL-37. In this study, we demonstrated that submicrocidal concentrations of LL-37 inhibit biofilm formation by A. actinomycetemcomitans and act as opsonins and agglutinins that greatly enhance its clearance by neutrophils and macrophages. Improved uptake of A. actinomycetemcomitans by neutrophils was mediated by their opsonization with LL-37. Enhanced phagocytosis and killing of A. actinomycetemcomitans by murine macrophage-like RAW 264.7 cells were dependent on their preagglutination by LL-37. Although A. actinomycetemcomitans is resistant to the bactericidal effect of LL-37, our results offer a rationale for the epidemiological association between LL-37 deficiency and the expansion of oral A. actinomycetemcomitans and indicate a possible therapeutic use of cationic peptides for host defense.

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Section: Resultssupporting

confidence: 87%

“…Surprisingly, although a lack of LL-37 was correlated with disease caused by A. actinomycetemcomitans overgrowth, this bacterium does not appear to be sensitive to LL-37 when tested in vitro (24). We therefore searched for additional mechanisms by which LL-37 might control the growth of A. actinomycetemcomitans in the oral cavity.…”

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confidence: 99%

LL-37 Opsonizes and Inhibits Biofilm Formation of Aggregatibacter actinomycetemcomitans at Subbactericidal Concentrations

et al. 2013

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“…The general mechanisms of microbial resistance to AMPs, which are valid both for the planktonic and sessile states, include mutations that affect the structure and charge distribution of the cytoplasmatic membrane, modifications to the lipopolysaccharide structure of Gram-negative bacteria, and active pumping of the AMPs out of the cell (Altman et al 2006). Specifically, it has been reported that Gram-negative bacteria have evolved mechanisms to remodel the composition of the outer membrane through modification of the LPS molecules (Miller et al 2005), which impairs LPS-binding AMPs.…”

Section: Biofilm Resistance To Antimicrobial Peptidesmentioning

confidence: 99%

New trends in peptide-based anti-biofilm strategies: a review of recent achievements and bioinformatic approaches

2012

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Antimicrobial peptides (AMPs) have a broad spectrum of activity and unspecific mechanisms of action. Therefore, they are seen as valid alternatives to overcome clinically relevant biofilms and reduce the chance of acquired resistance. This paper reviews AMPs and anti-biofilm AMP-based strategies and discusses ongoing and future work. Recent studies report successful AMP-based prophylactic and therapeutic strategies, several databases catalogue AMP information and analysis tools, and novel bioinformatics tools are supporting AMP discovery and design. However, most AMP studies are performed with planktonic cultures, and most studies on sessile cells test AMPs on growing rather than mature biofilms. Promising preliminary synergistic studies have to be consubstantiated and the study of functionalized coatings with AMPs must be further explored. Standardized operating protocols, to enforce the repeatability and reproducibility of AMP anti-biofilm tests, and automated means of screening and processing the ever-expanding literature are still missing.

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“…Porphyromonas gingivalis is an oral anaerobe and the pathogen most associated with chronic periodontal disease (16,18,42). P. gingivalis has previously been found to be highly resistant to antimicrobial peptides (1,33). The Arg-gingipains and Lys-gingipain cysteine proteases (cleaving after arginine and lysine, respectively) are among the major virulence factors expressed and secreted by P. gingivalis.…”

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confidence: 99%

Saliva Enables the Antimicrobial Activity of LL-37 in the Presence of Proteases of Porphyromonas gingivalis

et al. 2009

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Proteolysis is a common microbial virulence mechanism that enables the destruction of host tissue and evasion from host defense mechanisms. Antimicrobial peptides, also known as host defense peptides, are effector molecules of the innate immunity that demonstrate a broad range of antimicrobial and immunoregulatory activities. Deficiency of the human LL-37 antimicrobial peptide was previously correlated with severe periodontal disease. Porphyromonas gingivalis, the major pathogen associated with periodontitis, is highly proteolytic. In this study, P. gingivalis was found capable of degrading LL-37 by utilizing its arginine-specific gingipains. Saliva collected from volunteers with a healthy periodontium protected LL-37 from proteolysis by P. gingivalis. Salivary protection of LL-37 was heat resistant and specific and enabled LL-37 to inhibit growth of Escherichia coli in the presence of the P. gingivalis proteases. Previously, saliva and other body fluids have been shown to inhibit the antimicrobial activity of LL-37. Here we demonstrate that at a cost of a small reduction in the bactericidal activity of LL-37, saliva enables the antibacterial activity of LL-37 despite the presence of proteases secreted by the main periodontopathogen.Cationic antimicrobial peptides are components of the innate immunity that mediate a broad range of antimicrobial activity and play an important role in mucosal protection (48). In mammals, antimicrobial peptides also function as immunomodulators of the innate immune system that alter gene expression in host cells, induce or modulate chemokine and cytokine production, and elicit or inhibit proinflammatory responses (6,24,40,46). Since the recognition of their immunoregulatory functions, antimicrobial peptides are often referred to as host defense peptides. The ␣-and ␤-defensins, histatins, and LL-37 antimicrobial peptides play an important role in protection of the oral cavity (7,11,20,36). LL-37, the only human host defense peptide of the cathelicidin family, is cleaved extracellularly from its 18-kDa human cationic antimicrobial protein (hCAP18) precursor into the biologically active 37-amino-acid antimicrobial peptide.Periodontitis is a chronic inflammatory disease that leads to destruction of the attachment apparatus of the teeth. Deficiency of salivary LL-37 in patients with morbus Kostmann syndrome (36) or with Papillon-Lefevre syndrome (10) was previously correlated with severe periodontitis. Porphyromonas gingivalis is an oral anaerobe and the pathogen most associated with chronic periodontal disease (16,18,42). P. gingivalis has previously been found to be highly resistant to antimicrobial peptides (1, 33). The Arg-gingipains and Lys-gingipain cysteine proteases (cleaving after arginine and lysine, respectively) are among the major virulence factors expressed and secreted by P. gingivalis. Being positively charged, arginine and lysine are highly represented in host defense peptides, including LL-37 (which has five arginines and six lysines). Not surprisingly, P. gingivalis w...

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In vitro assessment of antimicrobial peptides as potential agents against several oral bacteria

Abstract: Our results support growing evidence suggesting the use of antimicrobial peptides for prevention and treatment of oral disease.

Cited by 114 publications

References 10 publications

LL-37 Opsonizes and Inhibits Biofilm Formation of Aggregatibacter actinomycetemcomitans at Subbactericidal Concentrations

LL-37 Opsonizes and Inhibits Biofilm Formation of Aggregatibacter actinomycetemcomitans at Subbactericidal Concentrations

New trends in peptide-based anti-biofilm strategies: a review of recent achievements and bioinformatic approaches

Saliva Enables the Antimicrobial Activity of LL-37 in the Presence of Proteases of Porphyromonas gingivalis

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