Ceragenins: A Class of Antiviral Compounds to Treat Orthopox Infections

Howell, Michael D.; Streib, Joanne E.; Kim, Byung Eui; Lesley, Leighann J.; Dunlap, A.; Geng, Dianliang; Feng, Yingbin; Savage, Paul B.; Leung, Donald Y.M.

doi:10.1038/jid.2009.120

Cited by 49 publications

(48 citation statements)

References 31 publications

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“…Topical administration of CSA-13 on vaccinia-inoculated mice resulted in a significant decrease in the number of satellite lesions, and preincubation of the virus with CSA-13 inhibited viral replication. Notably, in these studies, Howell et al [51] observed that treatment of human keratinocytes with CSA-13 induced LL-37 and beta-defensin 3 production.…”

Section: Mechanism Of Actionmentioning

confidence: 96%

“…The activities of AMPs against lipid-enveloped viruses has been well established, but a full description of their antiviral activities has not been realized [49,50]. Howell et al [51] studied the activities of ceragenins against vaccinia virus. They showed that CSA-13, at a concentration comparable to the human AMP, LL-37, caused viral disruption.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

“…Deficiencies in LL-37 may allow propagation of vaccinia virus (the live-virus vaccine for small pox) in humans. Howell et al [51] studied the antiviral activity of CSA-13 against vaccinia virus and showed that it inactivates 60%, 91% and 96% of the virus at 5, 10, and 25 µM, respectively. Microscopy of vaccinia virus with CSA-13 and LL-37 showed similar morphological changes to the virus with apparent damage to the envelope and internal structure.…”

Section: Antiviral Activitymentioning

confidence: 99%

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Ceragenins as Mimics of Endogenous Antimicrobial Peptides

Hashemi¹,

Holden²,

DurnaÅ³

et al. 2017

J Antimicrob Agents

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Ceragenins are small molecule mimics of endogenous antimicrobial peptides (AMPs), and as such display broadspectrum antimicrobial activity. These molecules are derived from a common bile acid and can be prepared at a large scale. Because ceragenins are not peptide based, they are not substrates for proteases. Gram-negative and positive bacteria are susceptible to ceragenins, including drug resistant organisms. Although ceragenins and colistin have common features, ceragenins retain full antibacterial activity against colistin-resistant Gram-negative bacteria. Bactericidal activity of ceragenins involves selective association with bacterial membranes followed by membrane depolarization. Due to this mechanism of action, which provides bactericidal activity against sessile bacteria, ceragenins eradicate established biofilms. Lipid-enveloped viruses (e.g. vaccinia) are deactivated by ceragenins, and topical application of a lead ceragenin decreases transmission of the virus in skin in a murine model. More recently, the activities of ceragenins against fungal pathogens have been reported, with minimum inhibition concentrations comparable to clinically used anti-fungal agents. In addition to antimicrobial activities, ceragenins have been shown to display some of the "secondary" activities attributed to AMPs. In vivo use of ceragenins to eradicate biofilms, prevent infection and accelerate bone growth demonstrate some of the types of applications in which ceragenins may be used to augment or replace activities of endogenous AMPs.

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Section: Mechanism Of Actionmentioning

confidence: 96%

Section: Mechanism Of Actionmentioning

confidence: 99%

Section: Antiviral Activitymentioning

confidence: 99%

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Ceragenins as Mimics of Endogenous Antimicrobial Peptides

Hashemi¹,

Holden²,

DurnaÅ³

et al. 2017

J Antimicrob Agents

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“…They are characterized by a broad spectrum of bactericidal activities against viruses, Gram-negative and Gram-positive bacteria (3)(4)(5), fungi, and parasites (6). Like that of natural CAPs, the bactericidal activity of ceragenins declines in the presence of blood plasma; the development of ceragenins is currently directed to topical applications (7)(8)(9).…”

mentioning

confidence: 99%

Bactericidal Activity of Ceragenin CSA-13 in Cell Culture and in an Animal Model of Peritoneal Infection

Bucki

Niemirowicz

Wnorowska

et al. 2015

Antimicrob Agents Chemother

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e Ceragenins constitute a novel family of cationic antibiotics characterized by a broad spectrum of antimicrobial activities, which have mostly been assessed in vitro. Using a polarized human lung epithelial cell culture system, we evaluated the antibacterial activities of the ceragenin CSA-13 against two strains of Pseudomonas aeruginosa (PAO1 and Xen5). Additionally, the biodistribution and bactericidal activity of a CSA-13-IRDye 800CW derivate were assessed using an animal model of peritoneal infection after PAO1 challenge. In cell culture, CSA-13 bactericidal activities against PAO1 and Xen5 were higher than the activities of the human cathelicidin peptide LL-37. Increased CSA-13 activity was observed in polarized human lung epithelial cell cultures subjected to butyric acid treatment, which is known to increase endogenous LL-37 production. Eight hours after intravenous or intraperitoneal injection, the greatest CSA-13-IRDye 800CW accumulation was observed in mouse liver and kidneys. CSA-13-IRDye 800CW administration resulted in decreased bacterial outgrowth from abdominal fluid collected from animals subjected to intraperitoneal PAO1 infection. These observations indicate that CSA-13 may synergistically interact with antibacterial factors that are naturally present at mucosal surfaces and it maintains its antibacterial activity in the infected abdominal cavity. Cationic lipids such as CSA-13 represent excellent candidates for the development of new antibacterial compounds.

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“…Significant activity of CSA-13 against cariogenic and periodontopathic bacteria correlate with its ability to bind bacteria lipopolysaccharide and lipoteichoic acid linked to erythrocytes [30]. CSA-13 is also active against vaccinia virus (VV) [31] and Trypanosoma cruzi [32]. Although some forms of ceragenins are effective against both Gram-negative and Gram-positive bacteria, they are generally more potent against Gram-positive bacteria (Figures 1 C and 1 D).…”

Section: Cerageninsmentioning

confidence: 99%

Ceragenins – a new weapon to fight multidrug resistant bacterial infections

Surel¹,

Niemirowicz²,

Marzec³

et al. 2014

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Growing antibiotic resistance among pathogenic microorganisms is one of the most challenging problems. Often, a single mutation in a bacterial cell leads to the formation of a new drug resistance mechanism. The ceragenins are a novel class of antibiotic, offering great promise in future treatment of infections. These cationic antimicrobial lipids are net positively charged cholic acid derivates that are electrostatically attracted to the negatively charged membranes of bacteria, certain viruses, fungi, and protozoa. After membrane insertion, they interfere with membrane organisation, resulting in membrane dysfunction and cell death. This review focuses on the broad spectrum of antibacterial activity of ceragenins, and their potential to become a new group of antibiotics for prevention and treatment of infections, especially those caused by multidrug-resistant bacteria. StreszczenieStale narastająca oporność bakterii na antybiotyki jest jednym z najtrudniejszych problemów. Często pojedyncza mutacja w komórce bakteryjnej prowadzi do powstania i rozwoju nowego mechanizmu, nadającego bakteriom oporność na antybiotyki. Cerageniny (pochodne kwasu cholowego) są analogami naturalnych kationowych peptydów przeciwbakteryjnych oferujących nowe możliwości w leczeniu infekcji bakteryjnych. Mają one dodatni ładunek powierzchniowy, dzięki czemu oddziałują elektrostatycznie z negatywnie naładowaną powierzchnią bakterii, wirusów, grzybów i pierwotniaków. Po insercji w strukturę lipidową błony mikroorganizmów zaburzają jej funkcję, co w efekcie prowadzi do śmierci komórki. W niniejszej pracy przedstawiono szerokie spektrum aktywności przeciwdrobnoustrojowej ceragenin i ich potencjał w zwalczaniu infekcji, w szczególności powodowanych przez wielooporne szczepy bakteryjne.

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Ceragenins: A Class of Antiviral Compounds to Treat Orthopox Infections

Cited by 49 publications

References 31 publications

Ceragenins as Mimics of Endogenous Antimicrobial Peptides

Ceragenins as Mimics of Endogenous Antimicrobial Peptides

Bactericidal Activity of Ceragenin CSA-13 in Cell Culture and in an Animal Model of Peritoneal Infection

Ceragenins – a new weapon to fight multidrug resistant bacterial infections

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