scholarly journals Host Defense Peptide Resistance Contributes to Colonization and Maximal Intestinal Pathology by Crohn's Disease-Associated Adherent-Invasive Escherichia coli

2014 ◽  
Vol 82 (8) ◽  
pp. 3383-3393 ◽  
Author(s):  
Joseph B. McPhee ◽  
Cherrie L. Small ◽  
Sarah A. Reid-Yu ◽  
John R. Brannon ◽  
Hervé Le Moual ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Host Defense ◽  
Bacterial Killing ◽  
Host Defense Peptides ◽  
Content Type ◽  
Host Defense Peptide ◽  
Defense Peptides ◽  
High Level

ABSTRACTHost defense peptides secreted by colonocytes and Paneth cells play a key role in innate host defenses in the gut. In Crohn's disease, the burden of tissue-associatedEscherichia colicommonly increases at epithelial surfaces where host defense peptides concentrate, suggesting that this bacterial population might actively resist this mechanism of bacterial killing. Adherent-invasiveE. coli(AIEC) is associated with Crohn's disease; however, the colonization determinants of AIEC in the inflamed gut are undefined. Here, we establish that host defense peptide resistance contributes to host colonization by Crohn's-associated AIEC. We identified a plasmid-encoded genomic island (called PI-6) in AIEC strain NRG857c that confers high-level resistance to α-helical cationic peptides and α- and β-defensins. Deletion of PI-6 sensitized strain NRG857c to these host defense molecules, reduced its competitive fitness in a mouse model of infection, and attenuated its ability to induce cecal pathology. This phenotype is due to two genes in PI-6,arlA, which encodes a Mig-14 family protein implicated in defensin resistance, andarlC, an OmpT family outer membrane protease. Implicit in these findings are new bacterial targets whose inhibition might limit AIEC burden and disease in the gut.

scholarly journals Characterization of two bacterial proteins (ArlA and ArlB) associated with resistance to host defense peptides

2021 ◽  
Author(s):  
Mario Antonio Vargas
Keyword(s):  
Host Defense ◽  
Pathogenic Bacteria ◽  
Genetic Locus ◽  
Core Gene ◽  
Two Component System ◽  
Host Defense Peptides ◽  
New Genes ◽  
Inflammatory Bowel ◽  
Defense Peptides ◽  
High Level

Inflammatory bowel disease is a complex condition with a multifactorial etiology. An interplay of various factors can lead to an inflamed gut with the overproduction of host-defense peptides (HDPs) and microbiome alterations, such as increases in pathogenic bacteria. Through processes involving either core gene regulation or acquisition of new genes, bacteria have evolved mechanisms to resist HDPs. Previously, a novel genetic locus, arlABC, was identified in adherent-invasive Escherichia coli (AIEC) strain NRG857c that contributes to high-level HDP resistance. ArlC is an outer membrane protease, but the function(s) of ArlA and ArlB are unknown. Thus, characterization was performed on strains mutated in these genes. Lipopolysaccharide gels suggest a change in the core structure of the mutant strains, but several phenotypic assays gave varying results. We demonstrate that the ArlB protein is regulated by the PhoPQ two-component system. We anticipate that these investigations will lead to a better understanding of HDP resistance in AIEC.

scholarly journals How Oxygen Availability Affects the Antimicrobial Efficacy of Host Defense Peptides: Lessons Learned from Studying the Copper-Binding Peptides Piscidins 1 and 3

2019 ◽  
Vol 20 (21) ◽  
pp. 5289 ◽  
Author(s):  
Adenrele Oludiran ◽  
David S. Courson ◽  
Malia D. Stuart ◽  
Anwar R. Radwan ◽  
John C. Poutsma ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Host Defense ◽  
Bacterial Species ◽  
Membrane Curvature ◽  
Lessons Learned ◽  
Health Concern ◽  
Copper Binding ◽  
Bacterial Killing ◽  
Host Defense Peptides ◽  
Defense Peptides

The development of new therapeutic options against Clostridioides difficile (C. difficile) infection is a critical public health concern, as the causative bacterium is highly resistant to multiple classes of antibiotics. Antimicrobial host-defense peptides (HDPs) are highly effective at simultaneously modulating the immune system function and directly killing bacteria through membrane disruption and oxidative damage. The copper-binding HDPs piscidin 1 and piscidin 3 have previously shown potent antimicrobial activity against a number of Gram-negative and Gram-positive bacterial species but have never been investigated in an anaerobic environment. Synergy between piscidins and metal ions increases bacterial killing aerobically. Here, we performed growth inhibition and time-kill assays against C. difficile showing that both piscidins suppress proliferation of C. difficile by killing bacterial cells. Microscopy experiments show that the peptides accumulate at sites of membrane curvature. We find that both piscidins are effective against epidemic C. difficile strains that are highly resistant to other stresses. Notably, copper does not enhance piscidin activity against C. difficile. Thus, while antimicrobial activity of piscidin peptides is conserved in aerobic and anaerobic settings, the peptide–copper interaction depends on environmental oxygen to achieve its maximum potency. The development of pharmaceuticals from HDPs such as piscidin will necessitate consideration of oxygen levels in the targeted tissue.

scholarly journals Efficacy of Antimicrobial Peptoids against Mycobacterium tuberculosis

2011 ◽  
Vol 55 (6) ◽  
pp. 3058-3062 ◽  
Author(s):  
Rinki Kapoor ◽  
Patrick R. Eimerman ◽  
Jonathan W. Hardy ◽  
Jeffrey D. Cirillo ◽  
Christopher H. Contag ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Cause Of Death ◽  
Host Defense ◽  
Natural Host ◽  
Antituberculosis Drug ◽  
Host Defense Peptides ◽  
Content Type ◽  
Defense Peptides

ABSTRACTTuberculosis is a leading cause of death worldwide. Resistance ofMycobacteriumto antibiotics can make treatments less effective in some cases. We tested selected oligopeptoids—previously reported as mimics of natural host defense peptides—for activity againstMycobacterium tuberculosisand assessed their cytotoxicity. A tetrameric, alkylated, cationic peptoid (1-C134mer) was most potent againstM. tuberculosisand least cytotoxic, whereas an unalkylated analogue, peptoid 14mer, was inactive. Peptoid 1-C134merthus merits further study as a potential antituberculosis drug.

scholarly journals Development of Heptylmannoside-Based Glycoconjugate Antiadhesive Compounds against Adherent-Invasive Escherichia coli Bacteria Associated with Crohn's Disease

mBio ◽  
2015 ◽  
Vol 6 (6) ◽  
Author(s):  
Adeline Sivignon ◽  
Xibo Yan ◽  
Dimitri Alvarez Dorta ◽  
Richard Bonnet ◽  
Julie Bouckaert ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial ◽  
Content Type ◽  
Type 1 Pili

ABSTRACTThe ileal lesions of Crohn's disease (CD) patients are colonized by adherent-invasiveEscherichia coli(AIEC) bacteria. These bacteria adhere to mannose residues expressed by CEACAM6 on host cells in a type 1 pilus-dependent manner. In this study, we investigated different antagonists of FimH, the adhesin of type 1 pili, for their ability to block AIEC adhesion to intestinal epithelial cells (IEC). Monovalent and multivalent derivatives ofn-heptyl α-d-mannoside (HM), a nanomolar antagonist of FimH, were testedin vitroin IEC infected with the AIEC LF82 strain andin vivoby oral administration to CEACAM6-expressing mice infected with LF82 bacteria.In vitro, multivalent derivatives were more potent than the monovalent derivatives, with a gain of efficacy superior to their valencies, probably owing to their ability to form bacterial aggregates. Of note, HM and the multi-HM glycoconjugates exhibited lower efficacyin vivoin decreasing LF82 gut colonization. Interestingly, HM analogues functionalized with an isopropylamide (1A-HM) or β-cyclodextrin pharmacophore at the end of the heptyl tail (1CD-HM) exerted beneficial effectsin vivo. These two compounds strongly decreased the amount of LF82 bacteria in the feces of mice and that of bacteria associated with the gut mucosa when administered orally at a dose of 10 mg/kg of body weight after infection. Importantly, signs of colitis and intestinal inflammation induced by LF82 infection were also prevented. These results highlight the potential of the antiadhesive compounds to treat CD patients abnormally colonized by AIEC bacteria and point to an alternative to the current approach focusing on blocking proinflammatory mediators.IMPORTANCECurrent treatments for Crohn's disease (CD), including immunosuppressive agents, anti-tumor necrosis factor alpha (anti-TNF-α) and anti-integrin antibodies, focus on the symptoms but not on the cause of the disease. Adherent-invasiveEscherichia coli(AIEC) bacteria abnormally colonize the ileal mucosa of CD patients via the interaction of the mannose-specific adhesin FimH of type 1 pili with CEACAM6 mannosylated proteins expressed on the epithelial cell surface. Thus, we decided to develop an antiadhesive strategy based on synthetic FimH antagonists specifically targeting AIEC bacteria that would decrease intestinal inflammation. Heptylmannoside (HM)-based glycocompounds strongly inhibit AIEC adhesion to intestinal epithelial cellsin vitro. The antiadhesive effect of two of these compounds of relatively simple chemical structure was also observedin vivoin AIEC-infected CEACAM6-expressing mice and was associated with a reduction in the signs of colitis. These results suggest a new therapeutic approach for CD patients colonized by AIEC bacteria, based on the development of synthetic FimH antagonists.

scholarly journals Structure-Activity Studies and Therapeutic Potential of Host Defense Peptides of Human Thrombin

2011 ◽  
Vol 55 (6) ◽  
pp. 2880-2890 ◽  
Author(s):  
Gopinath Kasetty ◽  
Praveen Papareddy ◽  
Martina Kalle ◽  
Victoria Rydengård ◽  
Matthias Mörgelin ◽  
...  
Keyword(s):  
Amino Acids ◽  
Antimicrobial Activity ◽  
Host Defense ◽  
Host Defense Peptides ◽  
Content Type ◽  
Peptide Epitopes ◽  
Structure Activity ◽  
Human Thrombin ◽  
Defense Peptides ◽  
Anti Inflammatory

ABSTRACTPeptides of the C-terminal region of human thrombin are released upon proteolysis and identified in human wounds. In this study, we wanted to investigate minimal determinants, as well as structural features, governing the antimicrobial and immunomodulating activity of this peptide region. Sequential amino acid deletions of the peptide GKYGFYTHVFRLKKWIQKVIDQFGE (GKY25), as well as substitutions at strategic and structurally relevant positions, were followed by analyses of antimicrobial activity against the Gram-negative bacteriaEscherichia coliandPseudomonas aeruginosa, the Gram-positive bacteriumStaphylococcus aureus, and the fungusCandida albicans. Furthermore, peptide effects on lipopolysaccharide (LPS)-, lipoteichoic acid-, or zymosan-induced macrophage activation were studied. The thrombin-derived peptides displayed length- and sequence-dependent antimicrobial as well as immunomodulating effects. A peptide length of at least 20 amino acids was required for effective anti-inflammatory effects in macrophage models, as well as optimal antimicrobial activity as judged by MIC assays. However, shorter (>12 amino acids) variants also displayed significant antimicrobial effects. A central K14 residue was important for optimal antimicrobial activity. Finally, one peptide variant, GKYGFYTHVFRLKKWIQKVI (GKY20) exhibiting improved selectivity, i.e., low toxicity and a preserved antimicrobial as well as anti-inflammatory effect, showed efficiency in mouse models of LPS shock andP. aeruginosasepsis. The work defines structure-activity relationships of C-terminal host defense peptides of thrombin and delineates a strategy for selecting peptide epitopes of therapeutic interest.

scholarly journals Identification of Synthetic and Natural Host Defense Peptides with Leishmanicidal Activity

2016 ◽  
Vol 60 (4) ◽  
pp. 2484-2491 ◽  
Author(s):  
A. K. Marr ◽  
S. Cen ◽  
R. E. W. Hancock ◽  
W. R. McMaster
Keyword(s):  
Host Defense ◽  
Leishmania Donovani ◽  
Leishmania Major ◽  
Public Health Problem ◽  
Major Public Health Problem ◽  
Host Defense Peptides ◽  
Content Type ◽  
Leishmanicidal Activity ◽  
Wide Range ◽  
Defense Peptides

ABSTRACTLeishmaniaparasites 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 ofLeishmania donovaniandLeishmania major. We also report that theLeishmaniaprotease/virulence factor GP63 confers protection toLeishmaniafrom the cytolytic properties of alll-form peptides (E6, L-1018, and LL-37) but not thed-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.

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

2013 ◽  
Vol 81 (10) ◽  
pp. 3577-3585 ◽  
Author(s):  
Asaf Sol ◽  
Ofir Ginesin ◽  
Stella Chaushu ◽  
Laila Karra ◽  
Shunit Coppenhagen-Glazer ◽  
...  
Keyword(s):  
Host Defense ◽  
Biofilm Formation ◽  
Aggregatibacter Actinomycetemcomitans ◽  
Bactericidal Effect ◽  
Raw 264.7 Cells ◽  
Gingival Tissue ◽  
Host Defense Peptides ◽  
Content Type ◽  
Major Mechanism ◽  
Defense Peptides

ABSTRACTHost 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 oralAggregatibacter actinomycetemcomitanswhich resulted in an aggressive periodontal disease. Surprisingly,A. actinomycetemcomitansshows resistance to high concentrations of LL-37. In this study, we demonstrated that submicrocidal concentrations of LL-37 inhibit biofilm formation byA. actinomycetemcomitansand act as opsonins and agglutinins that greatly enhance its clearance by neutrophils and macrophages. Improved uptake ofA. actinomycetemcomitansby neutrophils was mediated by their opsonization with LL-37. Enhanced phagocytosis and killing ofA. actinomycetemcomitansby murine macrophage-like RAW 264.7 cells were dependent on their preagglutination by LL-37. AlthoughA. actinomycetemcomitansis 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 oralA. actinomycetemcomitansand indicate a possible therapeutic use of cationic peptides for host defense.

scholarly journals Analysis of the σERegulon in Crohn's Disease-Associated Escherichia coli Revealed Involvement of thewaaWVLOperon in Biofilm Formation

2015 ◽  
Vol 197 (8) ◽  
pp. 1451-1465 ◽  
Author(s):  
Benoit Chassaing ◽  
Estelle Garénaux ◽  
Jessica Carriere ◽  
Nathalie Rolhion ◽  
Yann Guérardel ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Intestinal Mucosa ◽  
Biofilm Formation ◽  
Intestinal Epithelial ◽  
Content Type ◽  
E Coli ◽  
Gut Mucosa ◽  
Pathway Inhibition

ABSTRACTIleal lesions of patients with Crohn's disease are colonized by adherent-invasiveEscherichia coli(AIEC), which is able to adhere to and to invade intestinal epithelial cells (IEC), to replicate within macrophages, and to form biofilms on the surface of the intestinal mucosa. Previous analyses indicated the involvement of the σEpathway in AIEC-IEC interaction, as well as in biofilm formation, with σEpathway inhibition leading to an impaired ability of AIEC to colonize the intestinal mucosa and to form biofilms. The aim of this study was to characterize the σEregulon of AIEC strain LF82 in order to identify members involved in AIEC phenotypes. Using comparativein silicoanalysis of the σEregulon, we identified thewaaWVLoperon as a new member of the σEregulon in reference AIEC strain LF82. We determined that thewaaWVLoperon is involved in AIEC lipopolysaccharide structure and composition, and thewaaWVLoperon was found to be essential for AIEC strains to produce biofilm and to colonize the intestinal mucosa.IMPORTANCEAn increased prevalence of adherent-invasiveEscherichia coli(AIEC) bacteria was previously observed in the intestinal mucosa of Crohn's disease (CD) patients, and clinical observations revealed bacterial biofilms associated with the mucosa of CD patients. Here, analysis of the σEregulon in AIEC and commensalE. coliidentified 12 genes controlled by σEonly in AIEC. Among them, WaaWVL factors were found to play an essential role in biofilm formation and mucosal colonization by AIEC. In addition to identifying molecular tools that revealed a pathogenic population ofE. colicolonizing the mucosa of CD patients, these results indicate that targeting thewaaWVLoperon could be a potent therapeutic strategy to interfere with the ability of AIEC to form biofilms and to colonize the gut mucosa.

scholarly journals Potential of Host Defense Peptide Prodrugs as Neutrophil Elastase-Dependent Anti-Infective Agents for Cystic Fibrosis

2013 ◽  
Vol 58 (2) ◽  
pp. 978-985 ◽  
Author(s):  
Éanna Forde ◽  
Hilary Humphreys ◽  
Catherine M. Greene ◽  
Deirdre Fitzgerald-Hughes ◽  
Marc Devocelle
Keyword(s):  
Cystic Fibrosis ◽  
Host Defense ◽  
Bactericidal Activity ◽  
Neutrophil Elastase ◽  
Activity Levels ◽  
Host Defense Peptides ◽  
Content Type ◽  
Host Defense Peptide ◽  
Low Toxicity

ABSTRACTHost defense peptides (HDPs) are short antimicrobial peptides of the innate immune system. Deficiencies in HDPs contribute to enhanced susceptibility to infections, e.g., in cystic fibrosis (CF). Exogenous HDPs can compensate for these deficiencies, but their development as antimicrobials is limited by cytotoxicity. Three HDP prodrugs were designed so their net positive charge is masked by a promoiety containing a substrate for the enzyme neutrophil elastase (NE). This approach can confine activation to sites with high NE levels. Enzyme-labile peptides were synthesized, and their activation was investigated using purified NE. Susceptibilities ofPseudomonas aeruginosato parent and prodrug peptides in the presence and absence of NE-rich CF human bronchoalveolar lavage (BAL) fluid and different NaCl concentrations were compared. The effect of the HDP promoiety on cytotoxicity was determined with cystic fibrosis bronchial epithelial (CFBE41o-) cells. NE in CF BAL fluids activated the HDP prodrugs, restoring bactericidal activity against reference and clinical isolates ofP. aeruginosa. However, activation also required the addition of 300 mM NaCl. Under these conditions, the bactericidal activity levels of the HDP prodrugs differed, with pro-P18 demonstrating the greatest activity (90% to 100% of that of the parent, P18, at 6.25 μg/ml). Cytotoxic effects on CFBE41o- cells were reduced by the addition of the promoiety to HDPs. We demonstrate here for the first time the selective activation of novel HDP prodrugs by a host disease-associated enzyme atin vivoconcentrations of the CF lung. This approach may lead to the development of novel therapeutic agents with low toxicity that are active under the challenging conditions of the CF lung.

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