In vitro and in vivo evaluation of implantable bacterial-killing coatings based on host defense peptides and their synthetic mimics

2021 ◽  
Author(s):  
Yuxin Qian ◽  
Shuai Deng ◽  
Xue Wu ◽  
Yunrui She ◽  
Runhui Liu ◽  
...  
Keyword(s):  
Host Defense ◽  
In Vivo Evaluation ◽  
Bacterial Killing ◽  
Host Defense Peptides ◽  
Defense Peptides

scholarly journals Mechanistic Fingerprinting Reveals Kinetic Signatures of Resistance to Daptomycin and Host Defense Peptides in Streptococcus mitis-oralis

Antibiotics ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 404
Author(s):  
Michael R. Yeaman ◽  
Liana C. Chan ◽  
Nagendra N. Mishra ◽  
Arnold S. Bayer
Keyword(s):  
Flow Cytometry ◽  
Host Defense ◽  
Durable Resistance ◽  
Cross Resistance ◽  
Streptococcus Mitis ◽  
Host Defense Peptides ◽  
Strain Pair ◽  
Defense Peptides

Streptococcus mitis-oralis (S. mitis-oralis) infections are increasingly prevalent in specific populations, including neutropenic cancer and endocarditis patients. S. mitis-oralis strains have a propensity to evolve rapid, high-level and durable resistance to daptomycin (DAP-R) in vitro and in vivo, although the mechanism(s) involved remain incompletely defined. We examined mechanisms of DAP-R versus cross-resistance to cationic host defense peptides (HDPs), using an isogenic S. mitis-oralis strain-pair: (i) DAP-susceptible (DAP-S) parental 351-WT (DAP MIC = 0.5 µg/mL), and its (ii) DAP-R variant 351-D10 (DAP MIC > 256 µg/mL). DAP binding was quantified by flow cytometry, in-parallel with temporal (1–4 h) killing by either DAP or comparative prototypic cationic HDPs (hNP-1; LL-37). Multicolor flow cytometry was used to determine kinetic cell responses associated with resistance or susceptibility to these molecules. While overall DAP binding was similar between strains, a significant subpopulation of 351-D10 cells hyper-accumulated DAP (>2–4-fold vs. 351-WT). Further, both DAP and hNP-1 induced cell membrane (CM) hyper-polarization in 351-WT, corresponding to significantly greater temporal DAP-killing (vs. 351-D10). No strain-specific differences in CM permeabilization, lipid turnover or regulated cell death were observed post-exposure to DAP, hNP-1 or LL-37. Thus, the adaptive energetics of the CM appear coupled to the outcomes of interactions of S. mitis-oralis with DAP and selected HDPs. In contrast, altered CM permeabilization, proposed as a major mechanism of action of both DAP and HDPs, did not differentiate DAP-S vs. DAP-R phenotypes in this S. mitis-oralis strain-pair.

scholarly journals The Host Defense Peptide Beta-Defensin 1 Confers Protection against Bordetella pertussis in Newborn Piglets

2006 ◽  
Vol 74 (4) ◽  
pp. 2338-2352 ◽  
Author(s):  
Shokrollah Elahi ◽  
Rachelle M. Buchanan ◽  
Sam Attah-Poku ◽  
Hugh G. G. Townsend ◽  
Lorne A. Babiuk ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Host Defense ◽  
Bordetella Pertussis ◽  
Respiratory Infections ◽  
Upper Respiratory Tract ◽  
Host Defense Peptides ◽  
Newborn Piglets ◽  
Defense Peptides

ABSTRACT Innate immunity plays an important role in protection against respiratory infections in humans and animals. Host defense peptides such as beta-defensins represent major components of innate immunity. We recently developed a novel porcine model of pertussis, an important respiratory disease of young children and infants worldwide. Here, we investigated the role of porcine beta-defensin 1 (pBD-1), a porcine defensin homologue of human beta-defensin 2, in conferring protection against respiratory infection with Bordetella pertussis. In this model, newborn piglets were fully susceptible to infection and developed severe bronchopneumonia. In contrast, piglets older than 4 weeks of age were protected against infection with B. pertussis. Protection was associated with the expression of pBD-1 in the upper respiratory tract. In fact, pBD-1 expression was developmentally regulated, and the absence of pBD-1 was thought to contribute to the increased susceptibility of newborn piglets to infection with B. pertussis. Bronchoalveolar lavage specimens collected from older animals as well as chemically synthesized pBD-1 displayed strong antimicrobial activity against B. pertussis in vitro. Furthermore, in vivo treatment of newborn piglets with only 500 μg pBD-1 at the time of challenge conferred protection against infection with B. pertussis. Interestingly, pBD-1 displayed no bactericidal activity in vitro against Bordetella bronchiseptica, a closely related natural pathogen of pigs. Our results demonstrate that host defense peptides play an important role in protection against pertussis and are essential in modulating innate immune responses against respiratory infections.

Antiviral Activities of Human Host Defense Peptides

2020 ◽  
Vol 27 (9) ◽  
pp. 1420-1443 ◽  
Author(s):  
David C. Brice ◽  
Gill Diamond
Keyword(s):  
Host Defense ◽  
Broad Spectrum ◽  
Structural Features ◽  
Host Defense Peptides ◽  
Enveloped Viruses ◽  
Human Host ◽  
Wide Range ◽  
Defense Peptides

Peptides with broad-spectrum antimicrobial activity are found widely expressed throughout nature. As they participate in a number of different aspects of innate immunity in mammals, they have been termed Host Defense Peptides (HDPs). Due to their common structural features, including an amphipathic structure and cationic charge, they have been widely shown to interact with and disrupt microbial membranes. Thus, it is not surprising that human HDPs have activity against enveloped viruses as well as bacteria and fungi. However, these peptides also exhibit activity against a wide range of non-enveloped viruses as well, acting at a number of different steps in viral infection. This review focuses on the activity of human host defense peptides, including alpha- and beta-defensins and the sole human cathelicidin, LL-37, against both enveloped and non-enveloped viruses. The broad spectrum of antiviral activity of these peptides, both in vitro and in vivo suggest that they play an important role in the innate antiviral defense against viral infections. Furthermore, the literature suggests that they may be developed into antiviral therapeutic agents.

scholarly journals Host defense peptides for treatment of colorectal carcinoma - a comparative in vitro and in vivo analysis

Oncotarget ◽  
2014 ◽  
Vol 5 (12) ◽  
pp. 4467-4479 ◽  
Author(s):  
Claudia Maletzki ◽  
Ulrike Klier ◽  
Samuel Marinkovic ◽  
Ernst Klar ◽  
Jörg Andrä ◽  
...  
Keyword(s):  
Colorectal Carcinoma ◽  
Host Defense ◽  
Host Defense Peptides ◽  
In Vivo Analysis ◽  
Defense Peptides

scholarly journals Interplay between membrane active host defense peptides and heme modulates their assemblies and in vitro activity

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tünde Juhász ◽  
Mayra Quemé-Peña ◽  
Bence Kővágó ◽  
Judith Mihály ◽  
Maria Ricci ◽  
...  
Keyword(s):  
Lipid Bilayers ◽  
Host Defense ◽  
Great Promise ◽  
Microbial Infection ◽  
Host Defense Peptides ◽  
Membrane Activity ◽  
Defense Peptides ◽  
Bacterial Lipid

AbstractIn the emerging era of antimicrobial resistance, the susceptibility to co-infections of patients suffering from either acquired or inherited hemolytic disorders can lead to dramatic increase in mortality rates. Closely related, heme liberated during hemolysis is one of the major sources of iron, which is vital for both host and invading microorganisms. While recent intensive research in the field has demonstrated that heme exerts diverse local effects including impairment of immune cells functions, it is almost completely unknown how it may compromise key molecules of our innate immune system, such as antimicrobial host defense peptides (HDPs). Since HDPs hold great promise as natural therapeutic agents against antibiotic-resistant microbes, understanding the effects that may modulate their action in microbial infection is crucial. Here we explore how hemin can interact directly with selected HDPs and influence their structure and membrane activity. It is revealed that induced helical folding, large assembly formation, and altered membrane activity is promoted by hemin. However, these effects showed variations depending mainly on peptide selectivity toward charged lipids, and the affinity of the peptide and hemin to lipid bilayers. Hemin-peptide complexes are sought to form semi-folded co-assemblies, which are present even with model membranes resembling mammalian or bacterial lipid compositions. In vitro cell-based toxicity assays supported that toxic effects of HDPs could be attenuated due to their assembly formation. These results are in line with our previous findings on peptide-lipid-small molecule systems suggesting that small molecules present in the complex in vivo milieu can regulate HDP function. Inversely, diverse effects of endogenous compounds could also be manipulated by HDPs.

scholarly journals Host Defense Peptides in the Oral Cavity and the Lung: Similarities and Differences

2008 ◽  
Vol 87 (10) ◽  
pp. 915-927 ◽  
Author(s):  
G. Diamond ◽  
N. Beckloff ◽  
L.K. Ryan
Keyword(s):  
Oral Cavity ◽  
Host Defense ◽  
Gingival Crevicular Fluid ◽  
Immune Defense ◽  
The Body ◽  
Microbial Colonization ◽  
Host Defense Peptides ◽  
Innate Defense ◽  
Defense Peptides

Peptides with broad-spectrum antimicrobial activity are found in the mucosal surfaces at many sites in the body, including the airway, the oral cavity, and the digestive tract. Based on their in vitro antimicrobial and other immunomodulatory activities, these host defense peptides have been proposed to play an important role in the innate defense against pathogenic microbial colonization. The genes that encode these peptides are up-regulated by pathogens, further supporting their role in innate immune defense. However, the differences in the local microbial environments between the generally sterile airway and the highly colonized oral cavity suggest a more complex role for these peptides in innate immunity. For example, β-defensin genes are induced in the airway by all bacteria and Toll-like receptor (TLR) agonists primarily through an NF-κB-mediated pathway. In contrast, the same genes are induced in the gingival epithelium by only a subset of bacteria and TLR ligands, via different pathways. Furthermore, the environments into which the peptides are secreted—specifically saliva, gingival crevicular fluid, and airway surface fluid—differ greatly and can effect their respective activities in host defense. In this review, we examine the differences and similarities between host defense peptides in the oral cavity and the airway, to gain a better understanding of their contributions to immunity.

scholarly journals Collagen VI Contains Multiple Host Defense Peptides with Potent In Vivo Activity

2018 ◽  
Vol 201 (3) ◽  
pp. 1007-1020 ◽  
Author(s):  
Suado M. Abdillahi ◽  
Tobias Maaß ◽  
Gopinath Kasetty ◽  
Adam A. Strömstedt ◽  
Maria Baumgarten ◽  
...  
Keyword(s):  
Host Defense ◽  
Collagen Vi ◽  
Host Defense Peptides ◽  
Defense Peptides

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 Plasma gelsolin improves lung host defense against pneumonia by enhancing macrophage NOS3 function

2015 ◽  
Vol 309 (1) ◽  
pp. L11-L16 ◽  
Author(s):  
Zhiping Yang ◽  
Terry Ting-Yu Chiou ◽  
Thomas P. Stossel ◽  
Lester Kobzik
Keyword(s):  
Host Defense ◽  
Bacterial Pneumonia ◽  
Secondary Infection ◽  
Bacterial Clearance ◽  
Bacterial Killing ◽  
Plasma Gelsolin ◽  
Patients At Risk ◽  
Secondary Bacterial Pneumonia

Plasma gelsolin (pGSN) functions as part of the “extracellular actin-scavenging system,” but its potential to improve host defense against infection has not been studied. In a mouse model of primary pneumococcal pneumonia, recombinant human pGSN (rhu-pGSN) caused enhanced bacterial clearance, reduced acute inflammation, and improved survival. In vitro, rhu-pGSN rapidly improved lung macrophage uptake and killing of bacteria ( Streptococcus pneumoniae, Escherichia coli, and Francisella tularensis). pGSN triggers activating phosphorylation (Ser1177) of macrophage nitric oxide synthase type III (NOS3), an enzyme with important bactericidal functions in lung macrophages. rhu-pGSN failed to enhance bacterial killing by NOS3−/− macrophages in vitro or bacterial clearance in NOS3−/− mice in vivo. Prophylaxis with immunomodulators may be especially relevant for patients at risk for secondary bacterial pneumonia, e.g., after influenza. Treatment of mice with pGSN challenged with pneumococci on postinfluenza day 7 (the peak of enhanced susceptibility to secondary infection) caused a ∼15-fold improvement in bacterial clearance, reduced acute neutrophilic inflammation, and markedly improved survival, even without antibiotic therapy. pGSN is a potential immunomodulator for improving lung host defense against primary and secondary bacterial pneumonia.

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