Rhesus θ-defensin-1 (RTD-1) exhibitsin vitroandin vivoactivity against cystic fibrosis strains ofPseudomonas aeruginosa

Beringer, Paul M.; Bensman, Timothy J.; Ho, Henry C.; Agnello, Melissa; Denovel, Nicole; Nguyen, Albert; Wong-Beringer, Annie; She, Rosemary C.; Tran, Dat Q.; Moskowitz, Samuel M.; Selsted, Michael E.

doi:10.1093/jac/dkv301

Cited by 23 publications

(29 citation statements)

References 33 publications

(53 reference statements)

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“…RTD-1, the prototype -defensin, is well tolerated when administered systemically to mice and rats and is nonimmunogenic, highly stable, and effective in the arrest and resolution of autoimmune arthritis when administered as infrequently as once every 5 days (37,55). Further, studies presented here and previously reported (37,52,53,55,71) demonstrated that parenterally administered -defensins are well tolerated in mice and rats. Thus, the drug-like properties of naturally occurring -defensins represent a template for the development of antifungal agents that may prove valuable in the treatment of infections caused by MDR fungal pathogens.…”

Section: Efficacy Of -Defensins Against Mdr Candida Speciessupporting

confidence: 61%

“…Fifty microliters of 6% trifluoroacetic acid (TFA) was then added and incubated for 20 min at room temperature. Samples were clarified by centrifugation, supernatants were transferred to bovine serum albumin (BSA)-coated UPLC vials, and -defensin content was analyzed by UPLC-MS using an Acquity UPLC and Micromass Quattro Ultima mass spectrometer (Waters Corporation, Milford, MA), using RTD-1 as a standard, as previously described (71).…”

Section: Methodsmentioning

confidence: 99%

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Fungicidal Potency and Mechanisms of θ-Defensins against Multidrug-Resistant Candida Species

Basso

Garcia

Tran

et al. 2018

Antimicrob Agents Chemother

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Systemic candidiasis is a growing health care concern that is becoming even more challenging due to the growing frequency of infections caused by multidrug-resistant (MDR) species. Thus, there is an urgent need for new therapeutic approaches to candidiasis, including strategies bioinspired by insights into natural host defense against fungal pathogens. The antifungal properties of θ-defensins, macrocyclic peptides expressed in tissues of Old World monkeys, were investigated against a panel of drug-sensitive and drug-resistant clinical isolates of and non- species. Rhesus θ-defensin 1 (RTD-1), the prototype θ-defensin, was rapidly and potently fungicidal against drug-sensitive and MDR strains. Fungal killing occurred by cell permeabilization that was temporally correlated with ATP release and intracellular accumulation of reactive oxygen species (ROS). Killing by RTD-1 was compared with that by histatin 5 (Hst 5), an extensively characterized anticandidal peptide expressed in human saliva. RTD-1 killed much more rapidly and at a >200-fold lower concentration than that of Hst 5. Unlike Hst 5, the anticandidal activity of RTD-1 was independent of mitochondrial ATP production. Moreover, RTD-1 was completely resistant to proteases for 2 h under conditions that rapidly and completely degraded Hst 5. MICs and minimum fungicidal concentrations (MFCs) of 14 natural θ-defensins isoforms against drug-resistant isolates identified peptides that are more active than amphotericin B and/or caspofungin against fluconazole-resistant organisms, including MDR These results point to the potential of macrocyclic θ-defensins as structural templates for the design of antifungal therapeutics.

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Section: Efficacy Of -Defensins Against Mdr Candida Speciessupporting

confidence: 61%

Section: Methodsmentioning

confidence: 99%

Fungicidal Potency and Mechanisms of θ-Defensins against Multidrug-Resistant Candida Species

Basso

Garcia

Tran

et al. 2018

Antimicrob Agents Chemother

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“…A study conducted on a CFTR F508del-homozygous murine model of chronic P. aeruginosa lung infection indicated that treatment with Rhesus θ-defensin-1 significantly decreased lung infection and airway neutrophils [205]. Azithromycin-loaded and rapamycin-loaded nanocomposite microparticles a dry-powder-based antibiotic therapy, has been shown to enhance pulmonary antibiotic delivery [205, 206]. Recently, the use of phages, bacteria-specific viruses that kill pathogens has emerged as a promising alternative.…”

Section: Discussionmentioning

confidence: 99%

Cystic fibrosis lung environment and Pseudomonas aeruginosa infection

et al. 2016

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BackgroundThe airways of patients with cystic fibrosis (CF) are highly complex, subject to various environmental conditions as well as a distinct microbiota. Pseudomonas aeruginosa is recognized as one of the most important pulmonary pathogens and the predominant cause of morbidity and mortality in CF. A multifarious interplay between the host, pathogens, microbiota, and the environment shapes the course of the disease. There have been several excellent reviews detailing CF pathology, Pseudomonas and the role of environment in CF but only a few reviews connect these entities with regards to influence on the overall course of the disease. A holistic understanding of contributing factors is pertinent to inform new research and therapeutics.DiscussionIn this article, we discuss the deterministic alterations in lung physiology as a result of CF. We also revisit the impact of those changes on the microbiota, with special emphasis on P. aeruginosa and the influence of other non-genetic factors on CF. Substantial past and current research on various genetic and non-genetic aspects of cystic fibrosis has been reviewed to assess the effect of different factors on CF pulmonary infection. A thorough review of contributing factors in CF and the alterations in lung physiology indicate that CF lung infection is multi-factorial with no isolated cause that should be solely targeted to control disease progression. A combinatorial approach may be required to ensure better disease outcomes.ConclusionCF lung infection is a complex disease and requires a broad multidisciplinary approach to improve CF disease outcomes. A holistic understanding of the underlying mechanisms and non-genetic contributing factors in CF is central to development of new and targeted therapeutic strategies.

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“…2015; Beringer et al. 2016). Finally, the main direct mechanisms of action proposed for the cathelicidin LL-37 have been the bacterial membrane disruption following the toroidal pore model previously commented on and the probable interference with internal targets such as DNA (Xhindoli et al.…”

Section: Direct Mechanisms Of Actionmentioning

confidence: 99%

Perspectives for clinical use of engineered human host defense antimicrobial peptides

Pachón-Ibáñez

Smani

Pachón

et al. 2017

FEMS Microbiology Reviews

127

115

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Infectious diseases caused by bacteria, viruses or fungi are among the leading causes of death worldwide. The emergence of drug-resistance mechanisms, especially among bacteria, threatens the efficacy of all current antimicrobial agents, some of them already ineffective. As a result, there is an urgent need for new antimicrobial drugs. Host defense antimicrobial peptides (HDPs) are natural occurring and well-conserved peptides of innate immunity, broadly active against Gram-negative and Gram-positive bacteria, viruses and fungi. They also are able to exert immunomodulatory and adjuvant functions by acting as chemotactic for immune cells, and inducing cytokines and chemokines secretion. Moreover, they show low propensity to elicit microbial adaptation, probably because of their non-specific mechanism of action, and are able to neutralize exotoxins and endotoxins. HDPs have the potential to be a great source of novel antimicrobial agents. The goal of this review is to provide an overview of the advances made in the development of human defensins as well as the cathelicidin LL-37 and their derivatives as antimicrobial agents against bacteria, viruses and fungi for clinical use.

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Rhesus θ-defensin-1 (RTD-1) exhibitsin vitroandin vivoactivity against cystic fibrosis strains ofPseudomonas aeruginosa

Abstract: This study suggests that RTD-1 is a promising potential therapeutic agent for cystic fibrosis airway disease.

Cited by 23 publications

References 33 publications

Fungicidal Potency and Mechanisms of θ-Defensins against Multidrug-Resistant Candida Species

Fungicidal Potency and Mechanisms of θ-Defensins against Multidrug-Resistant Candida Species

Cystic fibrosis lung environment and Pseudomonas aeruginosa infection

Perspectives for clinical use of engineered human host defense antimicrobial peptides

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