In vitro evaluation of the potential for resistance development to ceragenin CSA-13

Pollard, Jake E.; Snarr, Jason; Chaudhary, Vinod; Jennings, Jacob D.; Shaw, Hannah; Christiansen, Bobbie; Wright, Jonathan O.; Jia, Wenyi; Bishop, Russell E.; Savage, Paul B.

doi:10.1093/jac/dks276

Cited by 75 publications

(71 citation statements)

References 35 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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“…Due to its high antibacterial activity, CSA-13 is the most promising ceragenin. A recent finding showed that CSA-13 retained potent antibacterial activity over the course of 30 serial passages, indicating that bacteria are very unlikely to develop resistance against this compound (10). In addition to bactericidal activity against planktonic bacteria, CSA-13 disintegrates bacterial biofilms in a very efficient manner, at a concentration slightly higher than that required for bactericidal activity against planktonic bacteria (11,12).…”

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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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“…This has led to many AMPs, such as pexiganan (analogue of magainin), gramicidins, polymyxin, nisin, daptomycin, and defensin-mimetic molecule, being entered into clinical trials (2)(3)(4)(5)(6). However, it has been argued in several in vitro studies and recent reports that the use of AMPs in therapeutic amounts over an extended period of time might lead to reduced susceptibility due to adaptive changes in phenotypic and genotypic characteristics of the organism (7)(8)(9)(10)(11)(12)(13). Therefore, the aim of our study was to examine whether S. aureus bacteria, on continuous exposure to sublethal concentrations of certain well-studied AMPs (magainin 2 and gramicidin D), alter their susceptibility and whether resistant strains are selected.…”

mentioning

confidence: 99%

Differential Adaptive Responses of Staphylococcus aureus to In Vitro Selection with Different Antimicrobial Peptides

Shireen

Singh

Das

et al. 2013

Antimicrob Agents Chemother

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We subjected Staphylococcus aureus ATCC 29213 to serial passage in the presence of subinhibitory concentrations of magainin 2 and gramicidin D for several hundred generations. We obtained S. aureus strains with induced resistance to magainin 2 (strain 55MG) and gramicidin D (strain 55GR) that showed different phenotypic changes in membrane properties. Both exhibited a change in membrane phospholipid content and an increase in membrane rigidity, while an alteration in net charge compared to that of the control occurred only in the case of 55MG.T he growing problem of resistance to conventional antibiotics in pathogens like Staphylococcus aureus and the need for new alternatives has stimulated interest in the development of antimicrobial peptides (AMPs) as human therapeutics (1). This has led to many AMPs, such as pexiganan (analogue of magainin), gramicidins, polymyxin, nisin, daptomycin, and defensin-mimetic molecule, being entered into clinical trials (2-6). However, it has been argued in several in vitro studies and recent reports that the use of AMPs in therapeutic amounts over an extended period of time might lead to reduced susceptibility due to adaptive changes in phenotypic and genotypic characteristics of the organism (7-13). Therefore, the aim of our study was to examine whether S. aureus bacteria, on continuous exposure to sublethal concentrations of certain well-studied AMPs (magainin 2 and gramicidin D), alter their susceptibility and whether resistant strains are selected. Since the putative mechanism of action of the AMPs studied involves targeting of the bacterial membrane, analyses of various cell membrane (CM) parameters were performed to understand their role in the in vitro-selected strains. (This study was presented in part at the 113th General Meeting, American Society for Microbiology, Denver, CO, 18 to 21 May 2013.) To generate AMP-resistant strains, S. aureus ATCC 29213 was chosen and two cell lines were maintained for each peptide in Mueller-Hinton broth (MHB). Serial passage was done in two cell lines for each AMP, one in the presence of noninhibitory and increasing AMP concentrations (positive-selection line) and the other in the absence of peptide (control selection line), as described elsewhere (10). The experiment was conducted for 55 serial passages, constituting 600 to 700 bacterial generations. Each transfer was given a strain designation to indicate the serial passage number. After every 5 transfers, evolution of resistance in the positive-selection line against magainin 2 and gramicidin D was identified by determining the MIC in MHB, following NCCLS guidelines (14). Further confirmation of resistance was done by performing a bactericidal assay as described before (15,16).The development of resistance occurred for both of the AMPs studied, as indicated by a gradual rise in MIC values with increasing passage number in the positive-selection lines compared to the MICs in the respective control selection lines. At the 55th passage, the positive-selection strains showed an Ն8-and ...

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In vitro evaluation of the potential for resistance development to ceragenin CSA-13

Abstract: CSA-13 retained potent antibacterial activity against S. aureus over the course of 30 serial passages. Resistance generated in Gram-negative bacteria correlates with modifications to the outer membranes of these organisms and was not stable outside of the presence of the antimicrobial.

Cited by 75 publications

References 35 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

Differential Adaptive Responses of Staphylococcus aureus to In Vitro Selection with Different Antimicrobial Peptides

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