Between good and evil:Complexation of the human cathelicidin LL-37 with nucleic acids

The innate immune system provides a crucial first line of defense against invading pathogens attacking the body. As the only member of the human cathelicidin family, the antimicrobial peptide LL-37 has been shown to have antiviral, antifungal, and antibacterial properties. In complexation with nucleic acids, LL-37 is suggested to maintain its beneficial health effects while also acting as a condensation agent for the nucleic acid. Complexes formed by LL-37 and nucleic acids have been shown to be immunostimulatory with a positive impact on the human innate immune system. However, some studies also suggest that in some circumstances, LL-37/nucleic acid complexes may be a contributing factor to autoimmune disorders such as psoriasis and systemic lupus erythematosus. This review provides a comprehensive discussion of research highlighting the beneficial health effects of LL-37/nucleic acid complexes, as well as discussing observed detrimental effects. We will emphasize why it is important to investigate and elucidate structural characteristics, such as condensation patterns of nucleic acids within complexation, and their mechanisms of action, to shed light on the intricate physiological effects of LL-37 and the seemingly contradictory role of LL-37/nucleic acid complexes in the innate immune response.</p

Role of Microbes in the Development of Alzheimer\u27s Disease: State of the Art - An International Symposium Presented at the 2017 IAGG Congress in San Francisco.

This article reviews research results and ideas presented at a special symposium at the International Association of Gerontology and Geriatrics (IAGG) Congress held in July 2017 in San Francisco. Five researchers presented their results related to infection and Alzheimer\u27s disease (AD). Prof. Itzhaki presented her work on the role of viruses, specifically HSV-1, in the pathogenesis of AD. She maintains that although it is true that most people harbor HSV-1 infection, either latent or active, nonetheless aspects of herpes infection can play a role in the pathogenesis of AD, based on extensive experimental evidence from AD brains and infected cell cultures. Dr. Miklossy presented research on the high prevalence of bacterial infections that correlate with AD, specifically spirochete infections, which have been known for a century to be a significant cause of dementia (e.g., in syphilis). She demonstrated how spirochetes drive senile plaque formation, which are in fact biofilms. Prof. Balin then described the involvement of brain tissue infection by th

Halogenation as a tool to tune antimicrobial activity of peptoids

Abstract Antimicrobial peptides have attracted considerable interest as potential new class of antibiotics against multi-drug resistant bacteria. However, their therapeutic potential is limited, in part due to susceptibility towards enzymatic degradation and low bioavailability. Peptoids (oligomers of N -substituted glycines) demonstrate proteolytic stability and better bioavailability than corresponding peptides while in many cases retaining antibacterial activity. In this study, we synthesized a library of 36 peptoids containing fluorine, chlorine, bromine and iodine atoms, which vary by length and level of halogen substitution in position 4 of the phenyl rings. As we observed a clear correlation between halogenation of an inactive model peptoid and its increased antimicrobial activity, we designed chlorinated and brominated analogues of a known peptoid and its shorter counterpart. Short brominated analogues displayed up to 32-fold increase of the activity against S. aureus and 16- to 64-fold against E. coli and P. aeruginosa alongside reduced cytotoxicity. The biological effect of halogens seems to be linked to the relative hydrophobicity and self-assembly properties of the compounds. By small angle X-ray scattering (SAXS) we have demontrated how the self-assembled structures are dependent on the size of the halogen, degree of substitution and length of the peptoid, and correlated these features to their activity

Membrane‐acting biomimetic peptoids against visceral leishmaniasis

Visceral leishmaniasis (VL) is among the most neglected tropical diseases in the world. Drug cell permeability is essential for killing the intracellular residing parasites responsible for VL, making cell-permeating peptides a logical choice to address VL. Unfortunately, the limited biological stability of peptides restricts their usage. Sequence-specific oligo-N-substituted glycines (‘peptoids’) are a class of peptide mimics that offers an excellent alternative to peptides in terms of ease of synthesis and good biostability. We tested peptoids against the parasite Leishmania donovani in both forms, that is, intracellular amastigotes and promastigotes. N-alkyl hydrophobic chain addition (lipidation) and bromination of oligopeptoids yielded compounds with good antileishmanial activity against both forms, showing the promise of these antiparasitic peptoids as potential drug candidates to treat VL

Role of Microbes in the Development of Alzheimer’s Disease: State of the Art – An International Symposium Presented at the 2017 IAGG Congress in San Francisco

This article reviews research results and ideas presented at a special symposium at the International Association of Gerontology and Geriatrics (IAGG) Congress held in July 2017 in San Francisco. Five researchers presented their results related to infection and Alzheimer’s disease (AD). Prof. Itzhaki presented her work on the role of viruses, specifically HSV-1, in the pathogenesis of AD. She maintains that although it is true that most people harbor HSV-1 infection, either latent or active, nonetheless aspects of herpes infection can play a role in the pathogenesis of AD, based on extensive experimental evidence from AD brains and infected cell cultures. Dr. Miklossy presented research on the high prevalence of bacterial infections that correlate with AD, specifically spirochete infections, which have been known for a century to be a significant cause of dementia (e.g., in syphilis). She demonstrated how spirochetes drive senile plaque formation, which are in fact biofilms. Prof. Balin then described the involvement of brain tissue infection by the Chlamydia pneumoniae bacterium, with its potential to use the innate immune system in its spread, and its initiation of tissue damage characteristic of AD. Prof. Fülöp described the role of AD-associated amyloid beta (Aβ) peptide as an antibacterial, antifungal and antiviral innate immune effector produced in reaction to microorganisms that attack the brain. Prof. Barron put forward the novel hypothesis that, according to her experiments, there is strong sequence-specific binding between the AD-associated Aβ and another ubiquitous and important human innate immune effector, the cathelicidin peptide LL-37. Given this binding, LL-37 expression in the brain will decrease Aβ deposition via formation of non-toxic, soluble Aβ/LL-37 complexes. Therefore, a chronic underexpression of LL-37 could be the factor that simultaneously permits chronic infections in brain tissue and allows for pathological accumulation of Aβ. This first-of-its-kind symposium opened the way for a paradigm shift in studying the pathogenesis of AD, from the “amyloid cascade hypothesis,” which so far has been quite unsuccessful, to a new “infection hypothesis,” or perhaps more broadly, “innate immune system dysregulation hypothesis,” which may well permit and lead to the discovery of new treatments for AD patients

Comblike, Monodisperse Polypeptoid Drag-Tags for DNA Separations by End-Labeled Free-Solution Electrophoresis (ELFSE)

The development of innovative technologies designed to reduce the cost and increase the throughput of DNA separations continues to be important for large-scale sequencing and genotyping efforts. We report research aimed at the further development of a free-solution bioconjugate method of DNA size separation by capillary electrophoresis (CE), in particular, the determination of an optimal molecular architecture for polyamide-based &quot;drag-tags&quot;. We synthesized several branched poly(N-methoxyethyl glycine)s (poly(NMEG)s, a class of polypeptoids) as novel friction-generating entities for end-on attachment to DNA molecules. A 30-mer poly(NMEG) &quot;backbone,&quot; comprising five evenly spaced reactive -amino groups, was synthesized on solid phase, cleaved, and purified to monodispersity by RP-HPLC. Three different comblike derivatives of this backbone molecule were created by (1) acetylating the -amino groups or (2) appending small, monodisperse NMEG oligomers (a tetramer and an octamer). Grafting of the oligo(NMEG)s was done using solution-phase amide bond formation chemistry. Once purified to total monodispersity, the three different drag-tags were studied by freesolution electrophoresis to observe the effect of branching on their hydrodynamic drag or &quot;R&quot; and hence their ability to separate DNA. Drag was found to scale linearly with total molecular weight, regardless of branch length. The octamer-branched drag-tag-DNA conjugate was used to separate ssDNA products of 50, 75, 100, and 150 bases in length by free-solution CE in less than 10 min. Hence, the use of branched or comblike drag-tags is both a feasible and an effective way to achieve high frictional drag, allowing the high-resolution separation of relatively large DNA molecules by free-solution CE without the need to synthesize very long polymers

Anti-persister and Anti-biofilm Activity of Self-Assembled Antimicrobial Peptoid Ellipsoidal Micelles

[Image: see text] Although persister cells are the root cause of resistance development and relapse of chronic infections, more attention has been focused on developing antimicrobial agents against resistant bacterial strains than on developing anti-persister agents. Frustratingly, the global preclinical antibacterial pipeline does not include any anti-persister drug. Therefore, the central point of this work is to explore antimicrobial peptidomimetics called peptoids (sequence-specific oligo-N-substituted glycines) as a new class of anti-persister drugs. In this study, we demonstrate that one particular antimicrobial peptoid, the sequence-specific pentamer TM5, is active against planktonic persister cells and sterilizes biofilms formed by both Gram-negative and Gram-positive bacteria. Moreover, we demonstrate the potential of TM5 to inhibit cytokine production induced by lipopolysaccharides from Gram-negative bacteria. We anticipate that this work can pave the way to the development of new anti-persister agents based on antimicrobial peptoids of this class to simultaneously help address the crisis of bacterial resistance and reduce the occurrence of the relapse of chronic infections

Efficacy of cathelicidin-mimetic antimicrobial peptoids against staphylococcus aureus

Staphylococcus aureus is one of the most common pathogens associated with infection in wounds. The current standard of care uses a combination of disinfection and drainage followed by conventional antibiotics such as methicillin. Methicillin and vancomycin resistance has rendered these treatments ineffective, often causing the reemergence of infection. This study examines the use of antimicrobial peptoids (sequence-specific poly-N-substituted glycines) designed to mimic naturally occurring cationic, amphipathic host defense peptides, as an alternative to conventional antibiotics. These peptoids also show efficient and fast (<30 min) killing of methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) at low micromolar concentrations without having apparent cytotoxic side effects in vivo. Additionally, these novel peptoids show excellent efficacy against biofilm formation and detachment for both MSSA and MRSA. In comparison, conventional antibiotics were unable to detach or prevent formation of biofilms. One cationic 12mer, Peptoid 1, shows great promise, as it could prevent formation of and detach biofilms at concentrations as low as 1.6 μM. The use of a bioluminescent S. aureus murine incision wound model demonstrated clearance of infection in peptoid-treated mice within 8 days, conveying another advantage these peptoids have over conventional antibiotics. These results provide clear evidence of the potential for antimicrobial peptoids for the treatment of S. aureus wound infections. IMPORTANCE Staphylococcus aureus resistance is a consistent problem with a large impact on the health care system. Infections with resistant S. aureus can cause serious adverse effects and can result in death. These antimicrobial peptoids show efficient killing of bacteria both as a biofilm and as free bacteria, often doing so in less than 30 min. As such, these antimicrobials have the potential to alleviate the burden that Staphylococcus infections have on the health care system and cause better outcomes for infected patients

The anti-inflammatory effects of photobiomodulation are mediated by cytokines: Evidence from a mouse model of inflammation

There is an urgent need for therapeutic approaches that can prevent or limit neuroinflammatory processes and prevent neuronal degeneration. Photobiomodulation (PBM), the therapeutic use of specific wavelengths of light, is a safe approach shown to have anti-inflammatory effects. The current study was aimed at evaluating the effects of PBM on LPS-induced peripheral and central inflammation in mice to assess its potential as an anti-inflammatory treatment. Daily, 30-min treatment of mice with red/NIR light (RL) or RL with a 40 Hz gamma frequency flicker for 10 days prior to LPS challenge showed anti-inflammatory effects in the brain and systemically. PBM downregulated LPS induction of key proinflammatory cytokines associated with inflammasome activation, IL-1β and IL-18, and upregulated the anti-inflammatory cytokine, IL-10. RL provided robust anti-inflammatory effects, and the addition of gamma flicker potentiated these effects. Overall, these results demonstrate the potential of PBM as an anti-inflammatory treatment that acts through cytokine expression modulation