Potent Inducers of Endogenous Antimicrobial Peptides for Host Directed Therapy of Infections

Ottosson, Håkan; Nylén, Frank; Sarker, Protim; Miraglia, Erica; Bergman, Peter; Guðmundsson, Guðmundur H.; Raqib, Rubhana; Agerberth, Birgitta; Strömberg, Roger

doi:10.1038/srep36692

Cited by 31 publications

(35 citation statements)

References 33 publications

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“…In addition, butyrates can work synergistically with vitamin D to induce additional AMPs. Recently, Ottosson et al [68] found new analogs aroylated phenylenediamines that can induce even more peptides. Importantly, in vivo efficacy of this approach has been demonstrated in a rabbit model for Shigellosis.…”

Section: Application Strategies Of Antimicrobial Peptidesmentioning

confidence: 99%

Host defense antimicrobial peptides as antibiotics: design and application strategies

Mishra

Reiling

Zarena

et al. 2017

Current Opinion in Chemical Biology

251

210

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This review deals with the design and application strategies of new antibiotics based on naturally occurring antimicrobial peptides (AMPs). The initial candidate can be designed based on three-dimensional structure or selected from a library of peptides from natural or laboratory sources followed by optimization via structure-activity relationship studies. There are also advanced application strategies such as induction of AMP expression from host cells by various factors (e.g., metals, amino acids, vitamin D and sunlight), the use of engineered probiotic bacteria to deliver peptides, the design of prodrug and peptide conjugates to improve specific targeting. In addition, combined uses of newly developed AMPs with existing antimicrobial agents may provide a practical avenue for effective management of antibiotic-resistant bacteria (superbugs, including biofilm). Finally, we highlight AMPs already in use or under clinical trials.

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Section: Application Strategies Of Antimicrobial Peptidesmentioning

confidence: 99%

Host defense antimicrobial peptides as antibiotics: design and application strategies

Mishra

Reiling

Zarena

et al. 2017

Current Opinion in Chemical Biology

251

210

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show abstract

“…We have previously developed a luciferase based screening assay in order to identify novel AMP-inducing compounds 19 . By using this assay we recently identified Entinostat and other related aroylated phenylendiamines (APDs) as potent inducers of LL-37, and that oral administration of Entinostat to a rabbit model of shigellosis clears the bacterial infection 20 . Entinostat is also known as a second generation HDAC inhibitor targeting class I HDACs and is currently being tested in clinical trials as an adjunctive therapy for various cancers 21 .…”

mentioning

confidence: 99%

Entinostat up-regulates the CAMP gene encoding LL-37 via activation of STAT3 and HIF-1α transcription factors

Miraglia

Nylén

Johansson

et al. 2016

Sci Rep

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Bacterial resistance against classical antibiotics is a growing problem and the development of new antibiotics is limited. Thus, novel alternatives to antibiotics are warranted. Antimicrobial peptides (AMPs) are effector molecules of innate immunity that can be induced by several compounds, including vitamin D and phenyl-butyrate (PBA). Utilizing a luciferase based assay, we recently discovered that the histone deacetylase inhibitor Entinostat is a potent inducer of the CAMP gene encoding the human cathelicidin LL-37. Here we investigate a mechanism for the induction and also find that Entinostat up-regulates human β-defensin 1. Analysis of the CAMP promoter sequence revealed binding sites for the transcription factors STAT3 and HIF-1α. By using short hairpin RNA and selective inhibitors, we found that both transcription factors are involved in Entinostat-induced expression of LL-37. However, only HIF-1α was found to be recruited to the CAMP promoter, suggesting that Entinostat activates STAT3, which promotes transcription of CAMP by increasing the expression of HIF-1α. Finally, we provide in vivo relevance to our findings by showing that Entinostat-elicited LL-37 expression was impaired in macrophages from a patient with a STAT3-mutation. Combined, our findings support a role for STAT3 and HIF-1α in the regulation of LL-37 expression.

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“…Entinostat was the strongest inducer in this class, and its treatment potential was subsequently tested in a rabbit model of shigellosis. We observed that oral administration of entinostat counteracted the downregulation of CAP-18, an effect that correlated with clinical recovery from shigellosis (19).…”

mentioning

confidence: 69%

“…Entinostat is a benzamide histone deacetylase inhibitor; hence, this activity could be included in the induction of LL-37. However, the much higher induction by entinostat and other APDs than by more-potent HDAC inhibitors (e.g., vorinostat and trichostatin A) suggests that HDAC inhibition cannot be the major route (19). Other mechanisms are likely to be responsible for the efficient induction of LL-37 by APDs.…”

Section: Discussionmentioning

confidence: 99%

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Treatment with Entinostat Heals Experimental Cholera by Affecting Physical and Chemical Barrier Functions of Intestinal Epithelia

Sarker

Banik

Strömberg

et al. 2017

Antimicrob Agents Chemother

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We have shown previously that oral treatment with sodium butyrate or phenylbutyrate in an experimental model of shigellosis improves clinical outcomes and induces the expression of the antimicrobial peptide CAP-18 in the large intestinal epithelia. In a subsequent study, we found that entinostat, an aroylated phenylenediamine compound, has similar therapeutic potential against shigellosis. In this study, we aimed to evaluate entinostat as a potential candidate for host-directed therapy against cholera in an experimental model. Vibrio cholerae-infected rabbits were treated with two different dose regimens of entinostat: either 0.5 mg twice daily for 2 days or 1 mg once daily for 2 days. The effects of treatment on clinical outcomes and V. cholerae shedding (CFU count in stool) were observed. Immunohistochemical analysis was carried out to assess CAP-18 expression in ileal and jejunal mucosae. The serum zonulin level was measured by an enzyme-linked immunosorbent assay (ELISA) to evaluate gut permeability. Infection of rabbits with V. cholerae downregulated CAP-18 expression in the ileal epithelium; the expression was replenished by oral treatment with entinostat at either dose regimen. The level of zonulin, a marker of gut permeability, in serum was upregulated after infection, and this upregulation was counteracted after treatment with entinostat. Entinostat treatment also led to recovery from cholera and a decline in the V. cholerae count in stool. In conclusion, the improved clinical outcome of cholera for rabbits treated with entinostat is associated with the induction of CAP-18 and the reduction of gut epithelial permeability.

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Potent Inducers of Endogenous Antimicrobial Peptides for Host Directed Therapy of Infections

Cited by 31 publications

References 33 publications

Host defense antimicrobial peptides as antibiotics: design and application strategies

Host defense antimicrobial peptides as antibiotics: design and application strategies

Entinostat up-regulates the CAMP gene encoding LL-37 via activation of STAT3 and HIF-1α transcription factors

Treatment with Entinostat Heals Experimental Cholera by Affecting Physical and Chemical Barrier Functions of Intestinal Epithelia

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