scholarly journals Identification of Synthetic Host Defense Peptide Mimics That Exert Dual Antimicrobial and Anti-Inflammatory Activities

2012 ◽  
Vol 19 (11) ◽  
pp. 1784-1791 ◽  
Author(s):  
Abhigyan Som ◽  
Nicolás Navasa ◽  
Avital Percher ◽  
Richard W. Scott ◽  
Gregory N. Tew ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Lipoteichoic Acid ◽  
Antibacterial Activities ◽  
Innate Immune Responses ◽  
Content Type ◽  
Host Defense Peptide ◽  
Anti Inflammatory ◽  
Molecular Patterns

ABSTRACTA group of synthetic antimicrobial oligomers, inspired by naturally occurring antimicrobial peptides, were analyzed for the ability to modulate innate immune responses to Toll-like receptor (TLR) ligands. These synthetic mimics of antimicrobial peptides (SMAMPs) specifically reduced cytokine production in response toStaphylococcus aureusand theS. aureuscomponent lipoteichoic acid (LTA), a TLR2 agonist. Anti-inflammatory SMAMPs prevented the induction of tumor necrosis factor (TNF), interleukin 6 (IL-6), and IL-10 in response toS. aureusor LTA, but no other TLR2 ligands. We show that these SMAMPs bind specifically to LTAin vitroand prevent its interaction with TLR2. Importantly, the SMAMP greatly reduced the induction of TNF and IL-6in vivoin mice acutely infected withS. aureuswhile simultaneously reducing bacterial loads dramatically (4 log10). Thus, these SMAMPs can eliminate the damage induced by pathogen-associated molecular patterns (PAMPs) while simultaneously eliminating infectionin vivo. They are the first known SMAMPs to demonstrate anti-inflammatory and antibacterial activitiesin vivo.

scholarly journals Combining Ceftriaxone with Doxycycline and Daptomycin Reduces Mortality, Neuroinflammation, Brain Damage, and Hearing Loss in Infant Rat Pneumococcal Meningitis

2019 ◽  
Vol 63 (7) ◽  
Author(s):  
Lukas Muri ◽  
Michael Perny ◽  
Jonas Zemp ◽  
Denis Grandgirard ◽  
Stephen L. Leib
Keyword(s):  
Adjuvant Therapy ◽  
Antibiotic Therapy ◽  
Brain Damage ◽  
Pneumococcal Meningitis ◽  
Therapeutic Option ◽  
Case Fatality ◽  
Content Type ◽  
Anti Inflammatory

ABSTRACTDespite appropriate antibiotic therapy, pneumococcal meningitis (PM) is associated with a case fatality rate of up to 30% in high-income countries. Survivors often suffer from severe lifelong disabilities. An excessive inflammatory reaction drives the pathophysiology, leading to brain damage and neurologic sequelae. We aimed to improve the outcome of experimental PM by simultaneously targeting different pathophysiological mechanisms with combined adjunctive therapies previously shown to be neuroprotective.In vitro, the anti-inflammatory effects of doxycycline and daptomycin were evaluated on primary rat astroglial cells stimulated withStreptococcus pneumoniae. Eleven-day-old infant Wistar rats were infected intracisternally withS. pneumoniaeand randomized for treatment with ceftriaxone or combination adjuvant therapy consisting of ceftriaxone, daptomycin, and doxycycline. During acute PM, combined-adjuvant therapy with ceftriaxone, daptomycin, and doxycycline increased the survival rate from 64.1% to 85.8% (P < 0.01) and alleviated weight loss compared to ceftriaxone monotherapy (P < 0.01). Levels of inflammatory cytokines were significantly reduced by combined-adjuvant therapyin vitro(P < 0.0001) and in cerebrospinal fluidin vivo(P < 0.05). In infected animals treated with combined adjunctive therapy, cortical damage was significantly reduced (P < 0.05), and animals showed a trend toward better hearing capacity 3 weeks after the infection (P = 0.089), an effect which was significant in mildly infected animals (48 decibels [dB] versus 67.22 dB;P < 0.05). These mildly infected animals showed significantly reduced cochlear fibrous occlusion (P < 0.01). By combining nonbacteriolytic daptomycin and anti-inflammatory doxycycline with ceftriaxone, the previously reported beneficial effects of the drugs were cumulated and identified the triple-antibiotic therapy as a promising therapeutic option for pediatric PM.

scholarly journals Antibacterial and Anti-Inflammatory Activity of an Antimicrobial Peptide Synthesized with D Amino Acids

Antibiotics ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 840
Author(s):  
Jlenia Brunetti ◽  
Veronica Carnicelli ◽  
Alessia Ponzi ◽  
Antonio Di Giulio ◽  
Anna Rita Lizzi ◽  
...  
Keyword(s):  
Amino Acids ◽  
Low Frequency ◽  
Lipoteichoic Acid ◽  
Isomeric Form ◽  
Multiresistant Pathogens ◽  
Gram Negative ◽  
Anti Inflammatory ◽  
Strong Candidate

The peptide SET-M33 is a molecule synthesized in tetra-branched form which is being developed as a new antibiotic against Gram-negative bacteria. Its isomeric form with D amino acids instead of the L version (SET-M33D) is also able to kill Gram-positive bacteria because of its higher resistance to bacterial proteases (Falciani et al., PLoS ONE, 2012, 7, e46259). Here we report the strong in vitro activity of SET-M33D (MIC range 0.7–6.0 µM) against multiresistant pathogens of clinical interest, including Gram-positives Staphylococcus aureus, Staphylococcus saprophyticus, and Enterococcus faecalis, and various Gram-negative enterobacteriaceae. SET-M33D antibacterial activity is also confirmed in vivo against a MRSA strain of S. aureus with doses perfectly compatible with clinical use (5 and 2.5 mg/Kg). Moreover, SET-M33D strongly neutralized lipopolysaccharide (LPS) and lipoteichoic acid (LTA), thus exerting a strong anti-inflammatory effect, reducing expression of cytokines, enzymes, and transcription factors (TNF-α, IL6, COX-2, KC, MIP-1, IP10, iNOS, NF-κB) involved in the onset and evolution of the inflammatory process. These results, along with in vitro and in vivo toxicity data and the low frequency of resistance selection reported here, make SET-M33D a strong candidate for the development of a new broad spectrum antibiotic.

scholarly journals Effective Control of Salmonella Infections by Employing Combinations of Recombinant Antimicrobial Human β-Defensins hBD-1 and hBD-2

2014 ◽  
Vol 58 (11) ◽  
pp. 6896-6903 ◽  
Author(s):  
Soumitra Maiti ◽  
Sunita Patro ◽  
Sukumar Purohit ◽  
Sumeet Jain ◽  
Shantibhusan Senapati ◽  
...  
Keyword(s):  
Bacterial Population ◽  
Antibacterial Activities ◽  
Effective Control ◽  
Content Type ◽  
E Coli ◽  
Salmonella Infections ◽  
Functional Peptides ◽  
Lethal Doses

ABSTRACTWe successfully produced two human β-defensins (hBD-1 and hBD-2) in bacteria as functional peptides and tested their antibacterial activities againstSalmonella entericaserovar Typhi,Escherichia coli, andStaphylococcus aureusemploying both spectroscopic and viable CFU count methods. Purified peptides showed approximately 50% inhibition of the bacterial population when used individually and up to 90% when used in combination. The 50% lethal doses (LD50) of hBD-1 againstS.Typhi,E. coli, andS. aureuswere 0.36, 0.40, and 0.69 μg/μl, respectively, while those for hBD-2 against the same bacteria were 0.38, 0.36, and 0.66 μg/μl, respectively. Moreover, we observed that bacterium-derived antimicrobial peptides were also effective in increasing survival time and decreasing bacterial loads in the peritoneal fluid, liver, and spleen of a mouse intraperitoneally infected withS.Typhi. The 1:1 hBD-1/hBD-2 combination showed maximum effectiveness in challenging theSalmonellainfectionin vitroandin vivo. We also observed less tissue damage and sepsis formation in the livers of infected mice after treatment with hBD-1 and hBD-2 peptides individually or in combination. Based on these findings, we conclude that bacterium-derived recombinant β-defensins (hBD-1 and hBD-2) are promising antimicrobial peptide (AMP)-based substances for the development of new therapeutics against typhoid fever.

scholarly journals Novel Synthetic (Poly)Glycerolphosphate-Based Antistaphylococcal Conjugate Vaccine

2013 ◽  
Vol 81 (7) ◽  
pp. 2554-2561 ◽  
Author(s):  
Quanyi Chen ◽  
Jay Dintaman ◽  
Andrew Lees ◽  
Goutam Sen ◽  
David Schwartz ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Conjugate Vaccine ◽  
Animal Studies ◽  
Lipoteichoic Acid ◽  
Gram Positive ◽  
Content Type ◽  
Cpg Oligodeoxynucleotides ◽  
Staphylococcal Infections

ABSTRACTStaphylococcal infections are a major source of global morbidity and mortality. Currently there exists no antistaphylococcal vaccine in clinical use. Previous animal studies suggested a possible role for purified lipoteichoic acid as a vaccine target for eliciting protective IgG to several Gram-positive pathogens. Since the highly conserved (poly)glycerolphosphate backbone of lipoteichoic acid is a major antigenic target of the humoral immune system during staphylococcal infections, we developed a synthetic method for producing glycerol phosphoramidites to create a covalent 10-mer of (poly)glycerolphosphate for potential use in a conjugate vaccine. We initially demonstrated that intactStaphylococcus aureuselicits murine CD4+T cell-dependent (poly)glycerolphosphate-specific IgM and IgG responsesin vivo. Naive mice immunized with a covalent conjugate of (poly)glycerolphosphate and tetanus toxoid in alum plus CpG-oligodeoxynucleotides produced high secondary titers of serum (poly)glycerolphosphate-specific IgG. Sera from immunized mice enhanced opsonophagocytic killing of liveStaphylococcus aureusin vitro. Mice actively immunized with the (poly)glycerolphosphate conjugate vaccine showed rapid clearance of staphylococcal bacteremiain vivorelative to mice similarly immunized with an irrelevant conjugate vaccine. In contrast to purified, natural lipoteichoic acid, the (poly)glycerolphosphate conjugate vaccine itself exhibited no detectable inflammatory activity. These data suggest that a synthetic (poly)glycerolphosphate-based conjugate vaccine will contribute to active protection against extracellular Gram-positive pathogens expressing this highly conserved backbone structure in their membrane-associated lipoteichoic acid.

scholarly journals Investigation of the Biological Activities and Characterization of Bioactive Constituents of Ophiorrhiza rugosa var. prostrata (D.Don) & Mondal Leaves through In Vivo, In Vitro, and In Silico Approaches

Molecules ◽  
2019 ◽  
Vol 24 (7) ◽  
pp. 1367 ◽  
Author(s):  
Md. Adnan ◽  
Md. Nazim Uddin Chy ◽  
A.T.M. Mostafa Kamal ◽  
Md Azad ◽  
Arkajyoti Paul ◽  
...  
Keyword(s):  
Biological Activities ◽  
Gastrointestinal Transit ◽  
Ethanol Extract ◽  
Indigenous Communities ◽  
Antibacterial Activities ◽  
Significant Inhibition ◽  
Bioactive Constituents ◽  
Anti Inflammatory

Ophiorrhiza rugosa var. prostrata is one of the most frequently used ethnomedicinal plants by the indigenous communities of Bangladesh. This study was designed to investigate the antidiarrheal, anti-inflammatory, anthelmintic and antibacterial activities of the ethanol extract of O. rugosa leaves (EEOR). The leaves were extracted with ethanol and subjected to in vivo antidiarrheal screening using the castor oil-induced diarrhea, enteropooling, and gastrointestinal transit models. Anti-inflammatory efficacy was evaluated using the histamine-induced paw edema test. In parallel, in vitro anthelmintic and antibacterial activities were evaluated using the aquatic worm and disc diffusion assays respectively. In all three diarrheal models, EEOR (100, 200 and 400 mg/kg) showed obvious inhibition of diarrheal stool frequency, reduction of the volume and weight of the intestinal contents, and significant inhibition of intestinal motility. Also, EEOR manifested dose-dependent anti-inflammatory activity. Anthelmintic action was deemed significant (P < 0.001) with respect to the onset of paralysis and helminth death. EEOR also resulted in strong zones of inhibition when tested against both Gram-positive and Gram-negative bacteria. GC-MS analysis identified 30 compounds within EEOR, and of these, 13 compounds documented as bioactive showed good binding affinities to M3 muscarinic acetylcholine, 5-HT3, tubulin and GlcN-6-P synthase protein targets in molecular docking experiments. Additionally, ADME/T and PASS analyses revealed their drug-likeness, likely safety upon consumption and possible pharmacological activities. In conclusion, our findings scientifically support the ethnomedicinal use and value of this plant, which may provide a potential source for future development of medicines.

scholarly journals Isolation Site Influences Virulence Phenotype of Serotype 14 Streptococcus pneumoniae Strains Belonging to Multilocus Sequence Type 15

2015 ◽  
Vol 83 (12) ◽  
pp. 4781-4790 ◽  
Author(s):  
Zarina Amin ◽  
Richard M. Harvey ◽  
Hui Wang ◽  
Catherine E. Hughes ◽  
Adrienne W. Paton ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Immune Responses ◽  
Sequence Type ◽  
Transcriptional Analysis ◽  
Innate Immune Responses ◽  
Pathogenic Potential ◽  
Content Type ◽  
Niche Adaptation

Streptococcus pneumoniaeis a diverse species causing invasive as well as localized infections that result in massive global morbidity and mortality. Strains vary markedly in pathogenic potential, but the molecular basis is obscured by the diversity and plasticity of the pneumococcal genome. We have previously reported thatS. pneumoniaeserotype 3 isolates belonging to the same multilocus sequence type (MLST) differed markedly inin vitroandin vivophenotypes, in accordance with the clinical site of isolation, suggesting stable niche adaptation within a clonal lineage. In the present study, we have extended our analysis to serotype 14 clinical isolates from cases of sepsis or otitis media that belong to the same MLST (ST15). In a murine intranasal challenge model, five ST15 isolates (three from blood and two from ears) colonized the nasopharynx to similar extents. However, blood and ear isolates exhibited significant differences in bacterial loads in other host niches (lungs, ear, and brain) at both 24 and 72 h postchallenge. In spite of these differences, blood and ear isolates were present in the lungs at similar levels at 6 h postchallenge, suggesting that early immune responses may underpin the distinct virulence phenotypes. Transcriptional analysis of lung tissue from mice infected for 6 h with blood isolates versus ear isolates revealed 8 differentially expressed genes. Two of these were exclusively expressed in response to infection with the ear isolate. These results suggest a link between the differential capacities to elicit early innate immune responses and the distinct virulence phenotypes of clonally relatedS. pneumoniaestrains.

scholarly journals Nanotherapeutic Modulation of Human Neural Cells and Glioblastoma in Organoids and Monocultures

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2434
Author(s):  
Issan Zhang ◽  
Paula Lépine ◽  
Chanshuai Han ◽  
María Lacalle-Aurioles ◽  
Carol X.-Q. Chen ◽  
...  
Keyword(s):  
In Vitro Models ◽  
Neural Cells ◽  
Dependent Manner ◽  
Lipocalin 2 ◽  
Human Microglia ◽  
Anti Inflammatory ◽  
Molecular Patterns ◽  
The Brain

Inflammatory processes in the brain are orchestrated by microglia and astrocytes in response to activators such as pathogen-associated molecular patterns, danger-associated molecular patterns and some nanostructures. Microglia are the primary immune responders in the brain and initiate responses amplified by astrocytes through intercellular signaling. Intercellular communication between neural cells can be studied in cerebral organoids, co-cultures or in vivo. We used human cerebral organoids and glioblastoma co-cultures to study glia modulation by dendritic polyglycerol sulfate (dPGS). dPGS is an extensively studied nanostructure with inherent anti-inflammatory properties. Under inflammatory conditions, lipocalin-2 levels in astrocytes are markedly increased and indirectly enhanced by soluble factors released from hyperactive microglia. dPGS is an effective anti-inflammatory modulator of these markers. Our results show that dPGS can enter neural cells in cerebral organoids and glial cells in monocultures in a time-dependent manner. dPGS markedly reduces lipocalin-2 abundance in the neural cells. Glioblastoma tumoroids of astrocytic origin respond to activated microglia with enhanced invasiveness, whereas conditioned media from dPGS-treated microglia reduce tumoroid invasiveness. Considering that many nanostructures have only been tested in cancer cells and rodent models, experiments in human 3D cerebral organoids and co-cultures are complementary in vitro models to evaluate nanotherapeutics in the pre-clinical setting. Thoroughly characterized organoids and standardized procedures for their preparation are prerequisites to gain information of translational value in nanomedicine. This study provides data for a well-characterized dendrimer (dPGS) that modulates the activation state of human microglia implicated in brain tumor invasiveness.

Synthesis of 1,3-benzoxazines Based on 2,4,4-trimethyl-7,2’,4’-trihydroxy Flavan: Antibacterial, Anti-inflammatory, Cyclooxygenase-2 Inhibition and Molecular Modelling Studies

2018 ◽  
Vol 16 (1) ◽  
pp. 58-65
Author(s):  
Issam A. Mohammed ◽  
Mahmood Ahmed ◽  
Rabia Ikram ◽  
Muhammad Muddassar ◽  
Muhammad Abdul Qadir ◽  
...  
Keyword(s):  
Condensation Reaction ◽  
Binding Mode ◽  
Antibacterial Activities ◽  
Cyclooxygenase 2 ◽  
Primary Amines ◽  
Docking Simulations ◽  
Cox 2 ◽  
Anti Inflammatory

Background: In the present study, the formation of 2, 4, 4-trimethyl-7,2’4’-trihydroxy flavan has been used as the key feature for the formation of new 1,3-benzoxazines. This reaction was carried out via Mannich-condensation reaction, the 7-hydroxy group of flavan was reacted with different primary amines in the presence of formaldehyde. Methods: All the synthesized compounds were characterized on the basis of FT-IR, NMR, MS and elemental analysis (CHN). Disk diffusion and 96-well plate assay methods were employed for the zone of inhibition and minimum inhibitory concentration determination, respectively to investigate the antibacterial activities. Results and Conclusion: Our studies showed that compound with electron withdrawing group on the benzene ring of 1,3-benzoxazines has promising antibacterial activities. An oral dose of 10 mg/kg body weight was administered to albino mice for acute toxicity of synthesized compounds. In vivo anti-inflammatory and in-vitro cyclooxygenase-2 (COX-2) studies showed that compound 11 was the most potent anti-inflammatory agent which inhibited induced edema by 62.7% while 68.7% inhibition of COX-2 was observed. The plausible binding mode of this compound in COX-2 enzyme was also determined using molecular docking simulations.

scholarly journals Protective Humoral Immunity Elicited by a Needle-Free Malaria Vaccine Comprised of a Chimeric Plasmodium falciparum Circumsporozoite Protein and a Toll-Like Receptor 5 Agonist, Flagellin

2013 ◽  
Vol 81 (12) ◽  
pp. 4350-4362 ◽  
Author(s):  
Daniel Carapau ◽  
Robert Mitchell ◽  
Adéla Nacer ◽  
Alan Shaw ◽  
Caroline Othoro ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Humoral Immunity ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Content Type ◽  
Interleukin 5 ◽  
Toll Like Receptor 5 ◽  
Molecular Patterns

ABSTRACTImmunization withPlasmodiumsporozoites can elicit high levels of sterile immunity, and neutralizing antibodies from protected hosts are known to target the repeat region of the circumsporozoite (CS) protein on the parasite surface. CS-based subunit vaccines have been hampered by suboptimal immunogenicity and the requirement for strong adjuvants to elicit effective humoral immunity. Pathogen-associated molecular patterns (PAMPs) that signal through Toll-like receptors (TLRs) can function as potent adjuvants for innate and adaptive immunity. We examined the immunogenicity of recombinant proteins containing a TLR5 agonist, flagellin, and either full-length or selected epitopes of thePlasmodium falciparumCS protein. Mice immunized with either of the flagellin-modified CS constructs, administered intranasally (i.n.) or subcutaneously (s.c.), developed similar levels of malaria-specific IgG1 antibody and interleukin-5 (IL-5)-producing T cells. Importantly, immunization via the i.n. but not the s.c. route elicited sporozoite neutralizing antibodies capable of inhibiting >90% of sporozoite invasionin vitroandin vivo, as measured using a transgenic rodent parasite expressingP. falciparumCS repeats. These findings demonstrate that functional sporozoite neutralizing antibody can be elicited by i.n. immunization with a flagellin-modifiedP. falciparumCS protein and raise the potential of a scalable, safe, needle-free vaccine for the 40% of the world's population at risk of malaria.

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