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Natural and synthetic cathelicidin peptides with anti-microbial and anti-biofilm activity against Staphylococcus aureus
Scott N Dean, Barney M Bishop, Monique L van Hoek
BMC Microbiology , 2011, DOI: 10.1186/1471-2180-11-114
Abstract: The helical human cathelicidin LL-37 was tested against S. aureus, and was found to exhibit effective anti-microbial, anti-attachment as well as anti-biofilm activity at concentrations in the low μg/ml range. The effect of peptide chirality and associated protease-resistance was explored through the use of an all-D amino acid peptide, D-LL-37, and in turn compared to scrambled LL-37. Helical cathelicidins have been identified in other animals such as the Chinese cobra, Naja atra (NA-CATH). We previously identified an 11-residue imperfectly repeated pattern (ATRA motif) within the sequence of NA-CATH. A series of short peptides (ATRA-1, -2, -1A), as well as a synthetic peptide, NA-CATH:ATRA1-ATRA1, were designed to explore the significance of the conserved residues within the ATRA motif for anti-microbial activity. The CD spectrum of NA-CATH and NA-CATH:ATRA1-ATRA1 revealed the structural properties of these peptides and suggested that helicity may factor into their anti-microbial and anti-biofilm activities.The NA-CATH:ATRA1-ATRA1 peptide inhibits the production of biofilm by S. aureus in the presence of salt, exhibiting anti-biofilm activity at lower peptide concentrations than NA-CATH, LL-37 and D-LL-37; and demonstrates low cytoxicity against host cells but does not affect bacterial attachment. The peptides utilized in this anti-biofilm approach may provide templates for a new group of anti-microbials and potential future topical therapeutics for treating chronic wound infections.Staphylococci are common commensal bacteria of the skin [1], as well as important pathogens in foreign-body infections [2]. The gram-positive Staphylococcus (S.) aureus is a major human pathogen. It is the cause of many nosocomial infections, including life-threatening diseases such as toxic shock syndrome, sepsis and endocarditis [3]. S. aureus infections account for approximately 19,000 deaths per year in the United States [4]. The emergence of multi-drug resistant strains of S. aureus
Recent Results from the HDMS Experiment  [PDF]
H. V. Klapdor-Kleingrothaus,L. Baudis,A. Dietz,G. Heusser,I. V. Krivosheina,B. Majorovits,St. Kolb,H. Strecker
Physics , 2001,
Abstract: The status of dark matter search with the HDMS experiment is reviewed. After one year of running the HDMS prototype detector in the Gran Sasso Underground Laboratory, the inner crystal of the detector has been replaced with a HPGe crystal of enriched 73Ge. The results of the operation of the HDMS prototype detector are discussed.
Role of Leukotrienes on Protozoan and Helminth Infections
Alexandre P. Rogerio,Fernanda F. Anibal
Mediators of Inflammation , 2012, DOI: 10.1155/2012/595694
Abstract: Leukotrienes (LTs), formed by the 5-lipoxygenase-(5-LO-) catalyzed oxidation of arachidonic acid, are lipid mediators that have potent proinflammatory activities. Pharmacologic or genetic inhibition of 5-LO biosynthesis in animals is associated with increased mortality and impaired clearance of bacteria, fungi, and parasites. LTs play a role in the control of helminth and protozoan infections by modulating the immune system and/or through direct cytotoxicity to parasites; however, LTs may also be associated with pathogenesis, such as in cerebral malaria and schistosomal granuloma. Interestingly, some proteins from the saliva of insect vectors that transmit protozoans and secreted protein from helminth could bind LTs and may consequently modulate the course of infection or pathogenesis. In addition, the decreased production of LTs in immunocompromised individuals might modulate the pathophysiology of helminth and protozoan infections. Herein, in this paper, we showed the immunomodulatory and pathogenic roles of LTs during the helminth and protozoan infections.
Cathelicidin-BF, a Snake Cathelicidin-Derived Antimicrobial Peptide, Could Be an Excellent Therapeutic Agent for Acne Vulgaris  [PDF]
Yipeng Wang, Zhiye Zhang, Lingling Chen, Huijuan Guang, Zheng Li, Hailong Yang, Jianxu Li, Dewen You, Haining Yu, Ren Lai
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0022120
Abstract: Cathelicidins are a family of antimicrobial peptides acting as multifunctional effector molecules in innate immunity. Cathelicidin-BF has been purified from the snake venoms of Bungarus fasciatus and it is the first identified cathelicidin antimicrobial peptide in reptiles. In this study, cathelicidin-BF was found exerting strong antibacterial activities against Propionibacterium acnes. Its minimal inhibitory concentration against two strains of P. acnes was 4.7 μg/ml. Cathelicidin-BF also effectively killed other microorganisms including Staphylococcus epidermidis, which was possible pathogen for acne vulgaris. Cathelicidin-BF significantly inhibited pro-inflammatory factors secretion in human monocytic cells and P. acnes-induced O2.? production of human HaCaT keratinocyte cells. Observed by scanning electron microscopy, the surfaces of the treated pathogens underwent obvious morphological changes compared with the untreated controls, suggesting that this antimicrobial peptide exerts its action by disrupting membranes of microorganisms. The efficacy of cathelicidin-BF gel topical administering was evaluated in experimental mice skin colonization model. In vivo anti-inflammatory effects of cathelicidin-BF were confirmed by relieving P. acnes-induced mice ear swelling and granulomatous inflammation. The anti-inflammatory effects combined with potent antimicrobial activities and O2.? production inhibition activities of cathelicidin-BF indicate its potential as a novel therapeutic option for acne vulgaris.
New approaches to the development of anti-protozoan drug candidates: a review of patents
Cunha, Elaine F. F. da;Ramalho, Teodorico C.;Mancini, Daiana T.;Fonseca, Emanuella M. B.;Oliveira, Aline A.;
Journal of the Brazilian Chemical Society , 2010, DOI: 10.1590/S0103-50532010001000002
Abstract: protozoan infections are parasitic diseases that affect hundreds of millions of people worldwide, but have been largely neglected for drug development because they affect poor people in poor regions of the world. most of the current drugs used to treat these diseases are decades old and have many limitations, including the emergence of drug resistance. this review will focus on the most recent developments, from 2001 to 2008, published in the field of patents and publications, paying particular attention to promising compounds acting against trypanosomiasis, leishmaniasis, malaria, toxoplasmosis, amebiasis, giardiasis, balantidiasis and pneumocystosis, their chemistry and biological evaluation, and to new chemical and pharmaceutical processes.
Antiviral Activity and Increased Host Defense against Influenza Infection Elicited by the Human Cathelicidin LL-37  [PDF]
Peter G. Barlow, Pavel Svoboda, Annie Mackellar, Anthony A. Nash, Ian A. York, Jan Pohl, Donald J. Davidson, Ruben O. Donis
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0025333
Abstract: The extensive world-wide morbidity and mortality caused by influenza A viruses highlights the need for new insights into the host immune response and novel treatment approaches. Cationic Host Defense Peptides (CHDP, also known as antimicrobial peptides), which include cathelicidins and defensins, are key components of the innate immune system that are upregulated during infection and inflammation. Cathelicidins have immunomodulatory and anti-viral effects, but their impact on influenza virus infection has not been previously assessed. We therefore evaluated the effect of cathelicidin peptides on disease caused by influenza A virus in mice. The human cathelicidin, LL-37, and the murine cathelicidin, mCRAMP, demonstrated significant anti-viral activity in vivo, reducing disease severity and viral replication in infected mice to a similar extent as the well-characterized influenza virus-specific antiviral drug zanamivir. In vitro and in vivo experiments suggested that the peptides may act directly on the influenza virion rather than via receptor-based mechanisms. Influenza virus-infected mice treated with LL-37 had lower concentrations of pro-inflammatory cytokines in the lung than did infected animals that had not been treated with cathelicidin peptides. These data suggest that treatment of influenza-infected individuals with cathelicidin-derived therapeutics, or modulation of endogenous cathelicidin production may provide significant protection against disease.
Differential Cathelicidin Expression in Duodenal and Gastric Biopsies from Tanzanian and German Patients  [PDF]
Dorothee Rogoll, Juergen Schauber, Koy K. Mheta, August Stich, Wolfgang Scheppach
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0022049
Abstract: Background Epithelial surfaces such as the gastrointestinal mucosa depend on expression of antimicrobial peptides like cathelicidin for immune defence against pathogens. The mechanisms behind mucosal cathelicidin regulation are incompletely understood. Methods Cathelicidin expression was analysed in duodenal, antral and corpus/fundic mucosal biopsies from African and German patients. Additionally, cathelicidin expression was correlated with Helicobacter pylori (HP) infection and the inflammatory status of the mucosa. Results High cathelicidin transcript abundance was detected in duodenal biopsies from African subjects. On the contrary, cathelicidin mRNA expression was either undetectable or very low in tissue specimens from German patients. Also, in the antrum and corpus/fundus regions of the stomach significantly higher cathelicidin transcript levels were measured in Tanzanian compared to German patients. In gastric biopsies from African patients cathelicidin expression was increased in HP positive compared to HP negative subjects. Additionally, the inflammatory status measured by IL-8 expression correlated well with the HP infection status. Conclusions A higher duodenal and gastric cathelicidin expression in African (compared with European) individuals may be due to upregulation by antigenic stimulation and may confer a higher resistance against enteric infections.
Snake Cathelicidin from Bungarus fasciatus Is a Potent Peptide Antibiotics  [PDF]
Yipeng Wang, Jing Hong, Xiuhong Liu, Hailong Yang, Rui Liu, Jing Wu, Aili Wang, Donghai Lin, Ren Lai
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003217
Abstract: Background Cathelicidins are a family of antimicrobial peptides acting as multifunctional effector molecules of innate immunity, which are firstly found in mammalians. Recently, several cathelicidins have also been found from chickens and fishes. No cathelicidins from other non-mammalian vertebrates have been reported. Principal Findings In this work, a cathelicidin-like antimicrobial peptide named cathelicidin-BF has been purified from the snake venoms of Bungarus fasciatus and its cDNA sequence was cloned from the cDNA library, which confirm the presence of cathelicidin in reptiles. As other cathelicidins, the precursor of cathelicidin-BF has cathelin-like domain at the N terminus and carry the mature cathelicidin-BF at the C terminus, but it has an atypical acidic fragment insertion between the cathelin-like domain and the C-terminus. The acidic fragment is similar to acidic domains of amphibian antimicrobial precursors. Phylogenetic analysis revealed that the snake cathelicidin had the nearest evolution relationship with platypus cathelicidin. The secondary structure of cathelicidin-BF investigated by CD and NMR spectroscopy in the presence of the helicogenic solvent TFE is an amphipathic α-helical conformation as many other cathelicidins. The antimicrobial activities of cathelicidin BF against forty strains of microorganisms were tested. Cathelicidin-BF efficiently killed bacteria and some fungal species including clinically isolated drug-resistance microorganisms. It was especially active against Gram-negative bacteria. Furthermore, it could exert antimicrobial activity against some saprophytic fungus. No hemolytic and cytotoxic activity was observed at the dose of up to 400 μg/ml. Cathelicidin-BF could exist stably in the mice plasma for at least 2.5 hours. Conclusion Discovery of snake cathelicidin with atypical structural and functional characterization offers new insights on the evolution of cathelicidins. Potent, broad spectrum, salt-independent antimicrobial activities make cathelicidin-BF an excellent candidate for clinical or agricultural antibiotics.
Vitamin D Induction of the Human Antimicrobial Peptide Cathelicidin in the Urinary Bladder  [PDF]
Olof Hertting,?sa Holm,Petra Lüthje,Hanna Brauner,Robert Dyrdak,Aino Fianu Jonasson,Peter Wiklund,Milan Chromek,Annelie Brauner
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015580
Abstract: The urinary tract is frequently being exposed to potential pathogens and rapid defence mechanisms are therefore needed. Cathelicidin, a human antimicrobial peptide is expressed and secreted by bladder epithelial cells and protects the urinary tract from infection. Here we show that vitamin D can induce cathelicidin in the urinary bladder. We analyzed bladder tissue from postmenopausal women for expression of cathelicidin, before and after a three-month period of supplementation with 25-hydroxyvitamin D3 (25D3). Cell culture experiments were performed to elucidate the mechanisms for cathelicidin induction. We observed that, vitamin D per se did not up-regulate cathelicidin in serum or in bladder tissue of the women in this study. However, when the bladder biopsies were infected with uropathogenic E. coli (UPEC), a significant increase in cathelicidin expression was observed after 25D3 supplementation. This observation was confirmed in human bladder cell lines, even though here, cathelicidin induction occurred irrespectively of infection. Vitamin D treated bladder cells exerted an increased antibacterial effect against UPEC and colocalization to cathelicidin indicated the relevance of this peptide. In the light of the rapidly growing problem of resistance to common urinary tract antibiotics, we suggest that vitamin D may be a potential complement in the prevention of UTI.
Status of the HDMS experiment, the GENIUS project and the GENIUS-TF  [PDF]
H. V. Klapdor-Kleingrothaus,B. Majorovits,L. Baudis,A. Dietz,G. Heusser,I. Krivosheina,H. Strecker
Physics , 2001,
Abstract: The status of dark matter search in Heidelberg is reviewed. After one year of running the HDMS prototype experiment in the Gran Sasso Underground Laboratory, the inner crystal of the detector has been replaced with a HPGe crystal of enriched 73Ge. The results of the operation of the HDMS prototype detector are discussed. In the light of the contradictive results from the CDMS and DAMA experiments the GENIUS-TF, a new experimental setup is proposed. The GENIUS-TF could probe the DAMA evidence region using the WIMP nucleus recoil signal and WIMP annual modulation signature simulataneously. Besides that it can prove some key parameters of the detector technique, to be implemented into the GENIUS setup and will in this sense be a first step towards the realization of the GENIUS experiment.
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