Activity of LL-37, CRAMP and antimicrobial peptide-derived compounds E2, E6 and CP26 against Mycobacterium tuberculosis

Rivas-Santiago, Bruno; Santiago, Cesar E. Rivas; Castañeda-Delgado, Julio Enrique; León-Contreras, Juan Carlos; Hancock, Robert E. W.; Hernández-Pando, Rogelio

doi:10.1016/j.ijantimicag.2012.09.015

Cited by 105 publications

(71 citation statements)

References 29 publications

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“…To validate the leishmanicidal activity of the host defense peptide LL-37 and the three synthetic peptides L-1018, RI-1018, and E6 against L. donovani promastigotes, two different viability assays were used: (i) a flow cytometry assay in combination with fluorescein diacetate (FDA) (i.e., live-cell) staining and (ii) a redox activity assay that determines the redox activity of mitochondria using resazurin (22). Both assays were done in M199 medium in the absence of heatinactivated FCS (Fig.…”

Section: Resultsmentioning

confidence: 99%

Identification of Synthetic and Natural Host Defense Peptides with Leishmanicidal Activity

Marr

Cen

Hancock

et al. 2016

Antimicrob Agents Chemother

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Leishmania parasites are a major public health problem worldwide. Effective treatment of leishmaniasis is hampered by the high incidence of adverse effects to traditional drug therapy and the emergence of resistance to current therapeutics. A vaccine is currently not available. Host defense peptides have been investigated as novel therapeutic agents against a wide range of pathogens. Here we demonstrate that the antimicrobial peptide LL-37 and the three synthetic peptides E6, L-1018, and RI-1018 exhibit leishmanicidal activity against promastigotes and intramacrophage amastigotes of Leishmania donovani and Leishmania major. We also report that the Leishmania protease/virulence factor GP63 confers protection to Leishmania from the cytolytic properties of all L-form peptides (E6, L-1018, and LL-37) but not the D-form peptide RI-1018. The results suggest that RI-1018, E6, and LL-37 are promising peptides to develop further into components for antileishmanial therapy. Protozoan parasites belonging to the genus Leishmania are a global health problem, especially in resource-poor areas of Africa, Asia, the Americas, and Europe. Leishmania parasites cause leishmaniasis, which is classified as a neglected tropical disease. An estimated 20 million people are affected worldwide, with 1.3 million new cases each year and 20,000 to 30,000 deaths occurring annually (1). Transmission of Leishmania to the mammalian host occurs during a blood meal of infected sand flies of the genera Phlebotomus or Lutzomyia (2). Clinical manifestations of leishmaniasis vary depending on the infecting Leishmania strain. Leishmania major primarily causes a cutaneous form, with infected individuals developing characteristic but self-healing open sores. In contrast, Leishmania donovani infection can lead to a more invasive visceral leishmaniasis, also called kala-azar, which is potentially fatal if untreated.Leishmania parasites have a complex, digenetic life cycle, alternating between an extracellular, flagellated promastigote form that develops in the gut of a sand fly, and an intracellular nonmotile amastigote form that replicates in the macrophages of mammalian hosts.To date, no Leishmania vaccine is available, and current therapy is based on traditional pentavalent antimonials with considerable adverse side effects (3). Recently, oral miltefosine was approved by the U.S. Food and Drug Administration, while liposomal amphotericin B is in clinical trials for treatment against cutaneous and visceral leishmaniasis (4, 5). In addition, the increasing incidence of drug resistance in Leishmania renders currently available treatment options ineffective and further drives the need for new therapeutic agents.Cationic host defense (antimicrobial) peptides have been identified as an important part of the host innate immune response in all living species and have broad-spectrum antimicrobial, including antileishmanial, activity (6, 7). The actions of host defense peptides range from direct killing of invading pathogens to immune response modulation (8). A v...

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Section: Resultsmentioning

confidence: 99%

Identification of Synthetic and Natural Host Defense Peptides with Leishmanicidal Activity

Marr

Cen

Hancock

et al. 2016

Antimicrob Agents Chemother

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“…We referenced the previous studies to determine the induction method of the colitis model (34)(35)(36) and a rough dose range of peptide first (36)(37)(38)(39)(40)(41)(42). We found that providing drinking water containing DSS induces colitis was one of the well-established experimental models for studying IBD (43).…”

Section: Discussionmentioning

confidence: 99%

Porcine β-Defensin 2 Attenuates Inflammation and Mucosal Lesions in Dextran Sodium Sulfate–Induced Colitis

Han¹,

Zhang

Xia

et al. 2015

The Journal of Immunology

133

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Intestinal permeability plays a critical role in the etiopathogenesis of ulcerative colitis. Defensins, including porcine β-defensin (pBD)2, are crucial antimicrobial peptides for gut protection owing to their antibacterial and immunomodulatory activities. The purpose of this study was to investigate the protective effects of pBD2 on mucosal injury and the disruption of the epithelial barrier during the pathological process of dextran sodium sulfate (DSS)–induced colitis. The effects and mechanism of pBD2 were evaluated both using a DSS-induced C57BL/6 mouse model and, in vitro, using Caco-2 and RAW264.7 cells. DSS-induced colitis was characterized by higher disease activity index, shortened colon length, elevated activities of myeloperoxidase and eosinophil peroxidase, histologic evidence of inflammation, and increased expression levels of TNF-α, IL-6, and IL-8. pBD2 increased the expression of zonula occludens-1, zonula occludens-2, claudin-1, mucin-1, and mucin-2 mRNA and proteins, and it decreased permeability to FITC-D, as well as apoptosis, in DSS-treated mice. pBD2 also decreased inflammatory infiltrates of the colon epithelium. In Caco-2 cells, pBD2 increased transepithelial electrical resistance and mucin mRNA expression, and it decreased the permeability of FITC-D while preserving the structural integrity of the tight junctions. The effects of pBD2 appeared to be through upregulation of the expression of genes associated with tight junctions and mucins, and by suppressing DSS-induced increases in inflammation, inducible NO synthase, cyclooxygenase-2, and apoptosis. These results show that pBD2 improves DSS-induced changes in mucosal lesions and paracellular permeability, possibly by affecting the activation of NF-κB signaling. The present study demonstrates that intrarectal administration of pBD2 may be a novel preventive option for ulcerative colitis.

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“…They were purchased directly from the American Type Culture Collection (ATCC) through The Global Bioresource Center. Mycobacterium tuberculosis H37Rv (ATCC 27294) [27] and M. tuberculosis muti-drug resistant strain (MDR) [28] were from the Medical Research Unit-Zacatecas belonging to the Mexican Institute of Social Security.…”

Section: Methodsmentioning

confidence: 99%

Characterization of Antibacterial and Hemolytic Activity of Synthetic Pandinin 2 Variants and Their Inhibition against Mycobacterium tuberculosis

et al. 2014

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The contention and treatment of Mycobacterium tuberculosis and other bacteria that cause infectious diseases require the use of new type of antibiotics. Pandinin 2 (Pin2) is a scorpion venom antimicrobial peptide highly hemolytic that has a central proline residue. This residue forms a structural “kink” linked to its pore-forming activity towards human erythrocytes. In this work, the residue Pro14 of Pin2 was both substituted and flanked using glycine residues (P14G and P14GPG) based on the low hemolytic activities of antimicrobial peptides with structural motifs Gly and GlyProGly such as magainin 2 and ponericin G1, respectively. The two Pin2 variants showed antimicrobial activity against E. coli, S. aureus, and M. tuberculosis. However, Pin2 [GPG] was less hemolytic (30%) than that of Pin2 [G] variant. In addition, based on the primary structure of Pin2 [G] and Pin2 [GPG], two short peptide variants were designed and chemically synthesized keeping attention to their physicochemical properties such as hydrophobicity and propensity to adopt alpha-helical conformations. The aim to design these two short antimicrobial peptides was to avoid the drawback cost associated to the synthesis of peptides with large sequences. The short Pin2 variants named Pin2 [14] and Pin2 [17] showed antibiotic activity against E. coli and M. tuberculosis. Besides, Pin2 [14] presented only 25% of hemolysis toward human erythrocytes at concentrations as high as 100 µM, while the peptide Pin2 [17] did not show any hemolytic effect at the same concentration. Furthermore, these short antimicrobial peptides had better activity at molar concentrations against multidrug resistance M. tuberculosis than that of the conventional antibiotics ethambutol, isoniazid and rifampicin. Therefore, Pin2 [14] and Pin2 [17] have the potential to be used as an alternative antibiotics and anti-tuberculosis agents with reduced hemolytic effects.

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Activity of LL-37, CRAMP and antimicrobial peptide-derived compounds E2, E6 and CP26 against Mycobacterium tuberculosis

Cited by 105 publications

References 29 publications

Identification of Synthetic and Natural Host Defense Peptides with Leishmanicidal Activity

Identification of Synthetic and Natural Host Defense Peptides with Leishmanicidal Activity

Porcine β-Defensin 2 Attenuates Inflammation and Mucosal Lesions in Dextran Sodium Sulfate–Induced Colitis

Characterization of Antibacterial and Hemolytic Activity of Synthetic Pandinin 2 Variants and Their Inhibition against Mycobacterium tuberculosis

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