Resistance of
            <i>Porphyromonas gingivalis</i>
            ATCC 33277 to Direct Killing by Antimicrobial Peptides Is Protease Independent

Bachrach, Gilad; Altman, Hamutal; Kolenbrander, Paul E.; Chalmers, Natalia I.; Gabai-Gutner, Michal; Mor, Amram; Friedman, Michael; Steinberg, Doron

doi:10.1128/aac.01271-07

Cited by 39 publications

(42 citation statements)

References 43 publications

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“…Indeed, it has been demonstrated recently that F. nucleatum, which is sensitive to LL-37 (1), enables P. gingivalis growth in saliva (35). "Group protection," where a resistant species in the multispecies dental biofilm protects another species that is sensitive to a host factor, has been suggested previously (2,22,28). Here we suggest a host countermeasure for such phenomena.…”

Section: Discussionmentioning

confidence: 63%

“…Previous experiments using a protease-resistant d enantiomer peptide, a protease-deficient P. gingivalis mutant, and a fluorescently labeled antimicrobial peptide revealed that resistance of P. gingivalis to direct killing by LL-37 is protease independent and results (at least partially) from the low affinity of antimicrobial peptides to P. gingivalis (2). Because proteolytic degradation of LL-37 is nonessential for survival of P. gingivalis, it was suggested that LL-37 proteolysis by P. gingivalis provides neighboring dental plaque species with resistance to LL-37, which in turn benefits P. gingivalis (2).…”

Section: Discussionmentioning

confidence: 99%

“…Because proteolytic degradation of LL-37 is nonessential for survival of P. gingivalis, it was suggested that LL-37 proteolysis by P. gingivalis provides neighboring dental plaque species with resistance to LL-37, which in turn benefits P. gingivalis (2). Indeed, it has been demonstrated recently that F. nucleatum, which is sensitive to LL-37 (1), enables P. gingivalis growth in saliva (35).…”

Section: Discussionmentioning

confidence: 99%

“…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 was found to be capable of degrading antimicrobial peptides in vitro and under ex vivo conditions with human serum (12) and of inactivating the antibacterial activity of LL-37 (2). Here, we report that saliva added under ex vivo conditions mimicking those in the oral environment protects the human LL-37 antimicrobial peptide from degradation and enables its antimicrobial activity in the presence of the proteases of P. gingivalis.…”

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confidence: 81%

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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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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 81%

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

et al. 2009

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“…Porphyromonas gingivalis is known to hydrolyze AMPs mainly by expressing robust proteolytic activity (27). However, Ouhara et al suggested that Porphyromonas gingivalis resistance to D-enantiomer peptides was independent of its proteolytic capacity (27,28). Thus, the mechanism of bacterial resistance to tachyplesin I requires further research.…”

Section: Discussionmentioning

confidence: 99%

Experimental Induction of Bacterial Resistance to the Antimicrobial Peptide Tachyplesin I and Investigation of the Resistance Mechanisms

Hong

Fei

2016

Antimicrob Agents Chemother

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Tachyplesin I is a 17-amino-acid cationic antimicrobial peptide (AMP) with a typical cyclic antiparallel ␤-sheet structure that is a promising therapeutic for infections, tumors, and viruses. To date, no bacterial resistance to tachyplesin I has been reported. To explore the safety of tachyplesin I as an antibacterial drug for wide clinical application, we experimentally induced bacterial resistance to tachyplesin I by using two selection procedures and studied the preliminary resistance mechanisms. Aeromonas hydrophila XS91-4-1, Pseudomonas aeruginosa CGMCC1.2620, and Escherichia coli ATCC 25922 and F41 showed resistance to tachyplesin I under long-term selection pressure with continuously increasing concentrations of tachyplesin I. In addition, P. aeruginosa and E. coli exhibited resistance to tachyplesin I under UV mutagenesis selection conditions. Cell growth and colony morphology were slightly different between control strains and strains with induced resistance. Cross-resistance to tachyplesin I and antimicrobial agents (cefoperazone and amikacin) or other AMPs (pexiganan, tachyplesin III, and polyphemusin I) was observed in some resistant mutants. Previous studies showed that extracellular protease-mediated degradation of AMPs induced bacterial resistance to AMPs. Our results indicated that the resistance mechanism of P. aeruginosa was not entirely dependent on extracellular proteolytic degradation of tachyplesin I; however, tachyplesin I could induce increased proteolytic activity in P. aeruginosa. Most importantly, our findings raise serious concerns about the long-term risks associated with the development and clinical use of tachyplesin I.A ntibiotic resistance in pathogenic bacteria and the emergence of superbacteria have attracted attention from health care workers worldwide. Antimicrobial peptides (AMPs) are promising candidates for development of novel alternative antibiotics. However, studies have indicated that some bacteria (especially human pathogens) are resistant to certain AMPs (1, 2), and bacterial resistance to cationic AMPs can arise through long and continual selection in the laboratory (3). Furthermore, some evidence demonstrates that bacteria can evolve resistance to AMPs after extended clinical application (4). Bacterial resistance to the AMPs nisin, pexiganan, and colistin has arisen through their clinical use. There is also evidence that pathogen resistance to AMPs may produce resistance to other AMPs with the same source and similar action mechanisms (5), or even to those with different sources and different action mechanisms (6, 7). Habets and Brockhurst previously reported that therapeutic use of pexiganan, representing a promising new class of AMPs, could drive the evolution of pathogens that are resistant to our own immunity peptides (6). Bacterial evolution of AMP resistance would greatly shorten and restrict the use of AMPs, so elucidation of the potential mechanisms of bacterial resistance to AMPs is required to inform the design of more effective drugs and to reduce the in...

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Interactions of two enantiomers of a designer antimicrobial peptide with structural components of the bacterial cell envelope

Aparicio

2021

Journal of Peptide Science

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Antimicrobial peptides (AMPs) have great potential in treating multi-drug resistant bacterial infections. The antimicrobial activity of D-enantiomers is significantly higher than L-enantiomers and sometimes selectively enhanced against Gram-positive bacteria. Unlike phospholipids in the bacterial plasma membrane, the role of other bacterial cell envelop components is often overlooked in the mode of action of AMPs. In this work, we explored the structural interactions between the main different structural components in Gram-negative/Gram-positive bacteria and the two enantiomers of a designer AMP, GL13K. We observed that both L-GL13K and D-GL13K formed self-assembled amyloid-like nanofibrils when the peptides interacted with lipopolysaccharide and lipoteichoic acid, components of the outer membrane of Gram-negative bacteria and cell wall of Gram-positive bacteria, respectively. Another cell wall component, peptidoglycan, showed strong interactions exclusively with D-GL13K and formed distinct laminar structures. This specific interaction between peptidoglycans and D-GL13K might contribute to the enhanced activity of D-GL13K against Gram-positive bacteria as they have a much thicker peptidoglycan layer than Gram-negative bacteria. A better understanding of the specific role of bacterial cell envelop components in the AMPs mechanism of action can guide the design of more effective Gram-selective AMPs.

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Resistance of Porphyromonas gingivalis ATCC 33277 to Direct Killing by Antimicrobial Peptides Is Protease Independent

Cited by 39 publications

References 43 publications

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

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

Experimental Induction of Bacterial Resistance to the Antimicrobial Peptide Tachyplesin I and Investigation of the Resistance Mechanisms

Interactions of two enantiomers of a designer antimicrobial peptide with structural components of the bacterial cell envelope

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