Antimicrobial Peptides and Skin: A Paradigm of Translational Medicine

Körting, Hans Christian; Schöllmann, Claudia; Stauss-Grabo, Manuela; Schäfer‐Korting, Monika

doi:10.1159/000341990

Cited by 32 publications

(43 citation statements)

References 181 publications

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“…Interestingly, both epithelial cells and neutrophils can produce LL-37 or CRAMP. These extracellular AMPs possess a broad spectrum of antimicrobial activity by inducing pore formation in the bacterial membrane and represent a potent first line of host defense (11,14). The strong antibacterial activity of AMPs has selected many bacterial species to evolve countermeasures for evading the same defense mechanism (15-17).…”

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confidence: 99%

Chlamydial Plasmid-Encoded Virulence Factor Pgp3 Neutralizes the Antichlamydial Activity of Human Cathelicidin LL-37

et al. 2015

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dChlamydia trachomatis infection in the lower genital tract can ascend to and cause pathologies in the upper genital tract, potentially leading to severe complications, such as tubal infertility. However, chlamydial organisms depleted of plasmid or deficient in the plasmid-encoded Pgp3 are attenuated in ascending infection and no longer are able to induce the upper genital tract pathologies, indicating a significant role of Pgp3 in chlamydial pathogenesis. We now report that C. trachomatis Pgp3 can neutralize the antichlamydial activity of human cathelicidin LL-37, a host antimicrobial peptide secreted by both genital tract epithelial cells and infiltrating neutrophils. Pgp3 bound to and formed stable complexes with LL-37. We further showed that the middle region of Pgp3 (Pgp3m) was responsible for both the binding to and neutralization of LL-37, suggesting that Pgp3m can be targeted for attenuating chlamydial pathogenicity or developed for blocking LL-37-involved non-genital-tract pathologies, such as rosacea and psoriasis. Thus, the current study has provided significant information for both understanding the mechanisms of chlamydial pathogenesis and developing novel therapeutic agents. Chlamydia trachomatis infection in women's lower genital tract can ascend to and cause inflammatory pathologies in the upper genital tract, resulting in complications such as ectopic pregnancy and tubal infertility (1, 2). However, the mechanisms of how the C. trachomatis organisms ascend to the upper genital tract remain unknown. It is thought that the organisms' ability to complete intracellular replication and to spread from cell to cell significantly contributes to chlamydial pathogenicity (3-6). Chlamydial intracellular infection starts with the entry of an infectious elementary body (EB) into an epithelial cell via pathogen-induced endocytosis (7,8). The endocytosed EB differentiates to a noninfectious but metabolically active reticulate body (RB). After replication, the progeny RBs differentiate back to EBs that exit the infected cells to invade adjacent cells (6). The spreading from cell to cell inevitably exposes the progeny EBs to the extracellular mucosal environment, in which numerous host defense molecules, such as antimicrobial peptides (AMPs), are available for attacking the extracellular EBs. It is unclear how the C. trachomatis EB organisms manage to overcome these host defense mechanisms to ascend to the upper genital tract.Cationic peptides that possess antimicrobial activities are defined as AMPs, which include human alpha-defensins (HADs) or human neutrophil peptides (HNPs), human beta-defensins (HBDs), and cathelicidin LL-37 (9-12). LL-37 is a C-terminal 37-amino-acid peptide starting with double leucines (LL) processed from human cationic antimicrobial protein 18 (hCAP; 18 kDa) that contains a highly conserved amino-terminal cathelinlike domain and a variable carboxy-terminal domain (9, 11). The mouse orthologue is called cathelin-related antimicrobial peptide (CRAMP) (13). HNPs are produced mainly by neu...

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Chlamydial Plasmid-Encoded Virulence Factor Pgp3 Neutralizes the Antichlamydial Activity of Human Cathelicidin LL-37

et al. 2015

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“…The triple combination used in this trial not only offers pain relief due to the sodium channel blocking agent benzocaine, but also antiviral and antimicrobial activity due to benzalkonium chloride and tyrothricin. The antiviral activity for benzalkonium chloride, as well as the antibacterial and antiviral property of tyrothricin, is known 18, 19, 20. Antiviral properties for the combination of all three compounds in Dorithricin ® have been recently confirmed in an in vitro model 21.…”

Section: Discussionmentioning

confidence: 99%

“…The authors tested Gram‐positive bacteria and yeast strains which all turned out to be highly susceptible to tyrothricin (MICs ≤ 4 mg/L), despite decade‐long use of the substance. The authors concluded, “No acquired resistance of the tested strains was determined.”54 Also, the topical usage on mucous membranes reviewed by Korting19 concluded, “in contrast to other antibiotics, AMPs (such as tyrothricin)” do not seem to propagate the development of antibiotic‐resistant micro‐organisms.”19 …”

Section: Discussionmentioning

confidence: 99%

“…As part of the innate immune system of vertebrates, AMPs have direct antimicrobial function, acting as mediators of inflammation and their antimicrobial spectrum covers Gram‐positive and ‐negative bacteria, in case of superinfection, as well as fungi and certain viruses 18, 19, 20. Recent studies revealed antiviral activity was also in the fixed triple combination 21…”

Section: Introductionmentioning

confidence: 99%

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Efficacy and safety of a triple active sore throat lozenge in the treatment of patients with acute pharyngitis: Results of a multi-centre, randomised, placebo-controlled, double-blind, parallel-group trial (DoriPha)

Palm¹,

Fuchs

Stammer

et al. 2018

Int J Clin Pract

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ObjectiveThe aim of this multi‐centre, randomised, double‐blind, placebo‐controlled trial was to compare the efficacy and safety of the fixed combination of 0.5 mg tyrothricin, 1.0 mg benzalkonium chloride, and 1.5 mg benzocaine (study drug marketed as Dorithricin®) in repeat dosing for 3 days to match placebo lozenges in the treatment of acute pharyngitis in adults.MethodsPatients (pts, aged ≥18 years) with acute pharyngitis, ie, non‐streptococcal sore throat and moderate‐to‐severe pain (intensity NRS ≥ 7; VAS ≥ 50) were assigned to study drug (n = 160) or matching placebo (n = 161). Efficacy was assessed by investigator for 2 hours post initial dose (p.i.d.), and 3 days later (Visit 2). Primary efficacy endpoint was the complete resolution of throat pain and difficulty in swallowing at Visit 2 (3 days p.i.d.). Safety and local tolerability were also assessed.ResultsSeventy‐two hours (p.i.d.), complete resolution of throat pain and difficulty in swallowing were achieved by 44.6% patients on study drug compared with 27.2% patients on placebo (difference 17.4% (CI [5.8%; 29.7%]; 64% improvement [GEE, P = 0.0022]).Until 2 hours p.i.d., reduction in symptoms was better with study drug (P < 0.005). Treatment satisfaction was higher with study drug (patients′/investigators′ assessment (78.9%/78.9% vs 55.0%/55.6% for placebo) and was well tolerated, overall safety profile was comparable to placebo.ConclusionThe strength of this randomised controlled trial lies in the endpoint of complete remission after 3 days p.i.d., especially in the light of other trials addressing acute pharyngitis. The results of this study show a significant benefit of the study drug over placebo in the treatment of acute pharyngitis. Local treatment with the fixed combination (0.5 mg tyrothricin, 1.0 mg benzalkonium chloride, and 1.5 mg benzocaine) provides a rapid analgesic effect and is effective in relieving both severe throat pain as well as difficulty in swallowing associated with acute pharyngitis leading to a 64% improved complete remission within 72 hours. The triple active combination is a suitable treatment option for patients in the self‐management of acute pharyngitis and sore throat. Clinical trial registration: ClinicalTrials.gov, NCT03323528.

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“…The foremost clinical features of psoriasis include a typical hyper-proliferation and abnormal differentiation of keratinocytes, which is associated with the excessive production of pro-inflammatory cytokines/chemokines and activated T cells and plasmacytoid dendritic cells (pDCs) 82) . The psoriatic skin produces almost all well-known AMPs/HDPs, including hBD-1, hBD-2, hBD-3, LL-37, S100A7, S100A8, S100A9, S100A15, RNase 7, lysozyme, elafin and SLPI 1) 2) .…”

Section: Amps/hdps In Psoriasismentioning

confidence: 99%

Novel Insight Into the Role of Antimicrobial (Host Defense) Peptides/Proteins in Human Skin Diseases

Niyonsaba

2016

Juntendo Medical Journal

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In addition to functioning as a physical barrier, the skin has evolved several innate defense mechanisms for the rapid recognition of and protection against harmful microorganisms. As a part of this process, the skin releases a vast and powerful arsenal of antimicrobial peptides/proteins (AMPs), also called host defense peptides/proteins (HDPs), which are key players in the cutaneous immune system. Although originally named antimicrobial peptides, recent evidence has demonstrated that AMPs/HDPs play additional roles in orchestrating the adaptive immune response, such as the regulation of inflammation, induction of cell proliferation and differentiation, regulation of cytokine/chemokine production, facilitation of cell migration, promotion of wound healing and regulation of tight junction barriers. Additionally, numerous skin diseases show altered expression of AMPs/HDPs in the lesional skin, suggesting the crucial roles of these molecules in the pathophysiology of skin diseases. The purpose of this review is to describe the current knowledge regarding some of the most common and well-known AMPs/HDPs derived from the skin, to discuss the regulation of their expression and their antimicrobial and immunomodulatory functions, and to outline their roles in various skin diseases. We believe that understanding the basic knowledge of skin-derived AMPs/HDPs would provide new insight into the pathophysiology of skin disorders and offer novel therapeutic opportunities for skin infectious diseases.

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Antimicrobial Peptides and Skin: A Paradigm of Translational Medicine

Cited by 32 publications

References 181 publications

Chlamydial Plasmid-Encoded Virulence Factor Pgp3 Neutralizes the Antichlamydial Activity of Human Cathelicidin LL-37

Chlamydial Plasmid-Encoded Virulence Factor Pgp3 Neutralizes the Antichlamydial Activity of Human Cathelicidin LL-37

Efficacy and safety of a triple active sore throat lozenge in the treatment of patients with acute pharyngitis: Results of a multi-centre, randomised, placebo-controlled, double-blind, parallel-group trial (DoriPha)

Novel Insight Into the Role of Antimicrobial (Host Defense) Peptides/Proteins in Human Skin Diseases

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