Potential synergy activity of the novel ceragenin, CSA-13, against clinical isolates of Pseudomonas aeruginosa, including multidrug-resistant P. aeruginosa

Chin, Judy N.; Jones, Ronald N.; Sader, Hélio S.; Savage, Paul B.; Rybak, Michael J.

doi:10.1093/jac/dkm457

Cited by 99 publications

(86 citation statements)

References 21 publications

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“…For example, ceragenins retain activity against methicillin-resistant Staphylococcus aureus, [21] colistin-resistant Klebsiella pneumoniae [22,23] and fluconazoleresistant Candida albicans [24] Efforts to generate resistance to selected ceragenins have resulted in relatively small changes in susceptibility, due to modifications of the lipid A portion of LPS, but high levels of resistance have not been observed [22,25]. Multiple in vivo studies have demonstrated that ceragenins are well tolerated in specific tissues and retain their antibacterial activities [26][27][28].…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

Ceragenins as Mimics of Endogenous Antimicrobial Peptides

Hashemi¹,

Holden²,

DurnaÅ³

et al. 2017

J Antimicrob Agents

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“…Potency of the ceragenins varies from compound to compound, based on side groups added, solubility, and degree of charge (with greater positive charge correlating with greater antimicrobial activity). Importantly, ceragenins can kill bacterial pathogens that are resistant to multiple antibiotics, including methicillin-resistant Staphylococcus aureus (9) and multidrug-resistant Pseudomonas aeruginosa (8). They are also acid stable and water soluble.…”

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confidence: 99%

Role of the HefC Efflux Pump inHelicobacter pyloriCholesterol-Dependent Resistance to Ceragenins and Bile Salts

et al. 2011

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The human gastric pathogen Helicobacter pylori modifies host cholesterol via glycosylation and incorporates the glycosylated cholesterol into its membrane; however, the benefits of cholesterol to H. pylori are largely unknown. We speculated that cholesterol in the H. pylori membrane might alter the susceptibility of these organisms to membrane-disrupting antibacterial compounds. To test this hypothesis, H. pylori strains were cultured in Ham's F-12 chemically defined medium in the presence or absence of cholesterol. The two cultures were subjected to overnight incubations with serial 2-fold dilutions of 10 bile salts and four ceragenins, which are novel bile salt derivatives that mimic membrane-disrupting activity of antimicrobial peptides. H. pylori cultured with cholesterol was substantially more resistant to seven of the bile salts and three ceragenins than H. pylori cultured without cholesterol. In most cases, these cholesterol-dependent differences ranged from 2 to 7 orders of magnitude; this magnitude depended on concentration of the agent. Cholesterol is modified by glycosylation using Cgt, a cholesteryl glycosyltransferase. Surprisingly, a cgt knockout strain still maintained cholesterol-dependent resistance to bile salts and ceragenins, indicating that cholesterol modification was not involved in resistance. We then tested whether three putative, paralogous inner membrane efflux pumps, HefC, HefF, or HefI, played a role. While HefF and HefI appeared unimportant, HefC was shown to play a critical role in the resistance to bile salts and ceragenins by multiple methods in multiple strain backgrounds. Thus, both cholesterol and the putative bile salt efflux pump HefC play important roles in H. pylori resistance to bile salts and ceragenins.

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“…40 Ceragenins possess strong bactericidal activity against Gram-positive and Gram-negative bacteria, including MDR strains. [41][42][43][44][45][46] Significant membrane activity of CSAs results in bacterial membrane permeabilization and depolarization. 44,47 Previous studies indicate that antimicrobial activity of ceragenins against Gram-negative bacteria is usually lower than the effects against Gram-positive species.…”

Section: Discussionmentioning

confidence: 99%

Core–shell magnetic nanoparticles display synergistic antibacterial effects against <em>Pseudomonas aeruginosa</em> and <em>Staphylococcus aureus</em> when combined with cathelicidin LL-37 or selected ceragenins

Niemirowicz¹,

Piktel²,

Wilczewska³

et al. 2016

IJN

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Core–shell magnetic nanoparticles (MNPs) are promising candidates in the development of new treatment methods against infections, including those caused by antibiotic-resistant pathogens. In this study, the bactericidal activity of human antibacterial peptide cathelicidin LL-37, synthetic ceragenins CSA-13 and CSA-131, and classical antibiotics vancomycin and colistin, against methicillin-resistant Staphylococcus aureus Xen 30 and Pseudomonas aeruginosa Xen 5, was assessed alone and in combination with core–shell MNPs. Fractional inhibitory concentration index and fractional bactericidal concentration index were determined by microdilution methods. The potential of combined therapy using nanomaterials and selected antibiotics was confirmed using chemiluminescence measurements. Additionally, the ability of tested agents to prevent bacterial biofilm formation was evaluated using crystal violet staining. In most conditions, synergistic or additive effects were observed when combinations of core–shell MNPs with ceragenins or classical antibiotics were used. Our study revealed that a mixture of membrane-active agents such as LL-37 peptide or ceragenin CSA-13 with MNPs potentialized their antibacterial properties and might be considered as a method of delaying and overcoming bacterial drug resistance.

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Potential synergy activity of the novel ceragenin, CSA-13, against clinical isolates of Pseudomonas aeruginosa, including multidrug-resistant P. aeruginosa

Abstract: CSA-13 showed concentration-dependent activity against clinical isolates of P. aeruginosa, including multidrug-resistant P. aeruginosa. The addition of cefepime or ciprofloxacin to CSA-13 enhanced bacterial kill, achieving early synergy.

Cited by 99 publications

References 21 publications

Ceragenins as Mimics of Endogenous Antimicrobial Peptides

Ceragenins as Mimics of Endogenous Antimicrobial Peptides

Role of the HefC Efflux Pump inHelicobacter pyloriCholesterol-Dependent Resistance to Ceragenins and Bile Salts

Core–shell magnetic nanoparticles display synergistic antibacterial effects against <em>Pseudomonas aeruginosa</em> and <em>Staphylococcus aureus</em> when combined with cathelicidin LL-37 or selected ceragenins

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Potential synergy activity of the novel ceragenin, CSA-13, against clinical isolates of Pseudomonas aeruginosa, including multidrug-resistant P. aeruginosa

Abstract: CSA-13 showed concentration-dependent activity against clinical isolates of P. aeruginosa, including multidrug-resistant P. aeruginosa. The addition of cefepime or ciprofloxacin to CSA-13 enhanced bacterial kill, achieving early synergy.

Cited by 99 publications

References 21 publications

Ceragenins as Mimics of Endogenous Antimicrobial Peptides

Ceragenins as Mimics of Endogenous Antimicrobial Peptides

Role of the HefC Efflux Pump inHelicobacter pyloriCholesterol-Dependent Resistance to Ceragenins and Bile Salts

Core&ndash;shell magnetic nanoparticles display synergistic antibacterial effects against <em>Pseudomonas aeruginosa</em> and <em>Staphylococcus aureus</em> when combined with cathelicidin LL-37 or selected ceragenins

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Core–shell magnetic nanoparticles display synergistic antibacterial effects against <em>Pseudomonas aeruginosa</em> and <em>Staphylococcus aureus</em> when combined with cathelicidin LL-37 or selected ceragenins