Activities of cholic acid-derived antimicrobial agents against multidrug-resistant bacteria

Schmidt, Erica J.; Boswell, John S.; Walsh, Joshua P.; Schellenberg, Matthew M.; Winter, Timothy W.; Li, Chunhong; Allman, Glenn W.; Savage, Paul B.

doi:10.1093/jac/47.5.671

Cited by 50 publications

(45 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As mimics of AMPs, ceragenins display broad-spectrum activity against Gram-negative and positive bacteria, including activity against drug-resistant organisms [33, [52][53][54]. Studies of bacteria susceptibility to ceragenins has focused on clinical isolates and bacteria, primarily clinical isolates, endemic to specific areas of the human body.…”

Section: Antibacterial Activitymentioning

confidence: 99%

Ceragenins as Mimics of Endogenous Antimicrobial Peptides

Hashemi¹,

Holden²,

DurnaÅ³

et al. 2017

J Antimicrob Agents

View full text Add to dashboard Cite

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.

show abstract

Section: Antibacterial Activitymentioning

confidence: 99%

Ceragenins as Mimics of Endogenous Antimicrobial Peptides

Hashemi¹,

Holden²,

DurnaÅ³

et al. 2017

J Antimicrob Agents

View full text Add to dashboard Cite

show abstract

“…At least partial activity described for DS may be expected from disubstituted DS (D2S). DS and D2S (20,22,37) share some structural and functional properties with squalamine, a membrane-active cationic steroid antibiotic (CSA) (34), and some previously described cholic acid antimicrobial derivatives (23,42). Squalamine, first isolated from tissues of the dogfish shark, and its analogues with different polyamines added to the 3-keto group by reductive amination (29) effectively kill different strains of bacteria, but mammals appear not to produce cationic steroids as antimicrobial factors (17).…”

mentioning

confidence: 99%

“…The bactericidal properties of these compounds are due to membrane disruption, and they display a moderate degree of selectivity for prokaryotic over eukaryotic membranes (40). Many cholic acid derivates, such as L-lysine, lysyl-lysine (4), cholic acid with basic amino acids (5,32), guanidine (41), and spermidine (13), were previously characterized as potent antimicrobial agents that kill a wide range of strains, including multidrug-resistant bacteria (42) and fungi (26). In addition to previously described steroidal conjugates (40), we found that D2S displays strong antibacterial activity with low lytic effect on eukaryotic plasma membranes (20) and inhibits the inflammatory response induced by bacterial wall products in vitro.…”

mentioning

confidence: 99%

Combined Antibacterial and Anti-Inflammatory Activity of a Cationic Disubstituted Dexamethasone-Spermine Conjugate

Bucki

Leszczyńska²,

Byfield

et al. 2010

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The rising number of antibiotic-resistant bacterial strains represents an emerging health problem that has motivated efforts to develop new antibacterial agents. Endogenous cationic antibacterial peptides (CAPs) that are produced in tissues exposed to the external environment are one model for the design of novel antibacterial compounds. Here, we report evidence that disubstituted dexamethasone-spermine (D2S), a cationic corticosteroid derivative initially identified as a by-product of synthesis of dexamethasone-spermine (

show abstract

“…Perturbation of the OM alone has been thought to result in bacterial killing, since immobilized PMB can disrupt the OM (41); however, alternate hypotheses concerning "self-promoted" uptake of the antibiotic and subsequent perturbation of the inner membrane (IM), culminating in bacterial lysis, have also been suggested (11, 64). The recognition that membrane-active antimicrobials have not yet been exploited adequately in the clinic has spurred the search for noncytolytic, selective bacterial membrane-permeabilizing agents, notable examples of which include cationic peptides (18,19) and smallmolecule PMB mimics (12,13,27,44). The use of cationic peptides as therapeutic agents is fraught with several potential problems, including large therapeutic doses (a consequence of high molecular weight), parenteral administration because of the lack of oral bioavailability, immunogenicity, and nonspecific cytotoxicity (60).…”

mentioning

confidence: 99%

Structural Correlates of Antibacterial and Membrane-Permeabilizing Activities in Acylpolyamines

Balakrishna

Wood

Nguyen

et al. 2006

Antimicrob Agents Chemother

View full text Add to dashboard Cite

A homologous series of mono-and bis-acyl polyamines with varying acyl chain lengths originally synthesized for the purpose of sequestering lipopolysaccharide were evaluated for antimicrobial activity to test the hypothesis that these bis-cationic amphipathic compounds may also bind to and permeabilize intact gramnegative bacterial membranes. Some compounds were found to possess significant antimicrobial activity, mediated via permeabilization of bacterial membranes. Structure-activity relationship studies revealed a strong dependence of the acyl chain length on antimicrobial potency and permeabilization activity. Homologated spermine, bis-acylated with C 8 or C 9 chains, was found to profoundly sensitize Escherichia coli to hydrophobic antibiotics such as rifampin. Nonspecific cytotoxicity is a potential drawback of these membranophilic compounds. However, the surface activity of these cationic amphipaths is strongly attenuated under physiological conditions via binding to serum albumin. Significant antibacterial activity is still retained in the presence of physiological concentrations of human serum albumin, suggesting that these compounds may serve as leads in the development of novel adjuncts to conventional antimicrobial chemotherapy.The accelerated emergence of many strains of multidrugresistant bacteria as a result of widespread use and misuse of antibiotics has mandated the urgent need for a renewed search for novel antibacterial agents. The presence of an outer membrane (OM) in gram-negative bacteria provides an effective protective barrier in these organisms (33, 34) to antimicrobial agents that may otherwise be active. For instance, it has been reported that in antibiotics of natural origin that are active against gram-positive bacteria, more than 90% lacked activity at a useful level against Escherichia coli (55). The barrier, formed by a divalent cation-cross-linked matrix (36, 40) of lipopolysaccharide (LPS) molecules on the outer leaflet of the OM (17, 48), can be breached by metal-chelating agents such as EDTA or via displacement of LPS-bound metals by polycations of diverse structural classes (20,36,40,54,57).Polymyxin B (PMB), a cyclic, pentacationic, amphipathic peptide antibiotic isolated from Bacillus polymyxa (49) is a prototype membrane-perturbing agent whose antibacterial action is manifested via its binding to the lipid A moiety of LPS. Perturbation of the OM alone has been thought to result in bacterial killing, since immobilized PMB can disrupt the OM (41); however, alternate hypotheses concerning "self-promoted" uptake of the antibiotic and subsequent perturbation of the inner membrane (IM), culminating in bacterial lysis, have also been suggested (11, 64). The recognition that membrane-active antimicrobials have not yet been exploited adequately in the clinic has spurred the search for noncytolytic, selective bacterial membrane-permeabilizing agents, notable examples of which include cationic peptides (18,19) and smallmolecule PMB mimics (12,13,27,44). The use of cationic peptides as...

show abstract

Activities of cholic acid-derived antimicrobial agents against multidrug-resistant bacteria

Cited by 50 publications

References 4 publications

Ceragenins as Mimics of Endogenous Antimicrobial Peptides

Ceragenins as Mimics of Endogenous Antimicrobial Peptides

Combined Antibacterial and Anti-Inflammatory Activity of a Cationic Disubstituted Dexamethasone-Spermine Conjugate

Structural Correlates of Antibacterial and Membrane-Permeabilizing Activities in Acylpolyamines

Contact Info

Product

Resources

About