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1.
Microbiologyopen ; 2(2): 318-25, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23436807

ABSTRACT

The formation of a Pseudomonas aeruginosa biofilm, a complex structure enclosing bacterial cells in an extracellular polymeric matrix, is responsible for persistent infections in cystic fibrosis patients leading to a high rate of morbidity and mortality. The protective environment created by the tridimensional structure reduces the susceptibility of the bacteria to conventional antibiotherapy. Cationic steroid antibiotics (CSA)-13, a nonpeptide mimic of antimicrobial peptides with antibacterial activity on planktonic cultures, was evaluated for its ability to interact with sessile cells. Using confocal laser scanning microscopy, we demonstrated that the drug damaged bacteria within an established biofilm showing that penetration did not limit the activity of this antimicrobial agent against a biofilm. When biofilms were grown during exposure to shear forces and to a continuous medium flow allowing the development of robust structures with a complex architecture, CSA-13 reached the bacteria entrapped in the biofilm within 30 min. The permeabilizing effect of CSA-13 could be associated with the death of the bacteria. In static conditions, the compound did not perturb the architecture of the biofilm. This study confirms the potential of CSA-13 as a new strategy to combat persistent infections involving biofilms formed by P. aeruginosa.


Subject(s)
Anti-Infective Agents/pharmacology , Biofilms/drug effects , Pseudomonas aeruginosa/drug effects , Steroids/pharmacology , Biofilms/growth & development , Cystic Fibrosis/drug therapy , Cystic Fibrosis/microbiology , Humans , Microbial Sensitivity Tests , Microscopy, Confocal , Pseudomonas aeruginosa/growth & development
2.
J Parasitol ; 96(3): 638-42, 2010 Jun.
Article in English | MEDLINE | ID: mdl-19958044

ABSTRACT

Cationic steroid antibiotics (CSAs), or ceragenins, are amphiphilic compounds consisting of a cholic acid backbone that is attached to several cationic amines. In this study, we tested the hypothesis that CSAs possess antiparasitic activities with minimal to no effects on mammalian cells, and thus could be used as potential therapeutic agents against pathogenic trypanosomatids. To investigate this notion, we synthesized CSAs and determined their trypanocidal and leishmanicidal activities in vitro. The 3 ceragenins assayed, i.e., CSA-8, CSA-13, and CSA-54, showed several degrees of parasiticidal activity. CSA-13 was the most effective compound against Leishmania major promastigotes and Trypanosoma cruzi trypomastigotes, at LD(50) 4.9 and 9 microM, respectively. The trypanocidal activities of these ceragenins were also assessed by infectivity experiments. We found CSA-8 was more effective on T. cruzi intracellular amastigotes when the infected host cells were treated for 24 hr (LD(50), 6.7 microM). Macrophages and LLC-MK(2) (treated for 72 hr) showed relative low susceptibility to these compounds. Our results suggest that ceragenins are indeed promising chemotherapeutic agents against trypanosomatids, but they require further investigation.


Subject(s)
Leishmania major/drug effects , Steroids/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Analysis of Variance , Animals , Cell Line , Cells, Cultured , Lethal Dose 50 , Macaca mulatta , Macrophages/cytology , Macrophages/drug effects , Macrophages/parasitology , Mice , Steroids/chemistry , Steroids/toxicity , Trypanocidal Agents/chemistry , Trypanocidal Agents/toxicity
3.
J Invest Dermatol ; 129(11): 2668-75, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19516269

ABSTRACT

Eczema vaccinatum is a potentially fatal, disseminated viral skin infection that develops in individuals with atopic dermatitis after exposure to the vaccinia virus (VV). Despite advances in modern medicine, there are few options for those suffering from disseminated VV infections. Ceragenins (CSAs) are synthetic antimicrobial compounds designed to mimic the structure and function of endogenous antimicrobial peptides (AMPs). We show that CSA-13 exhibits potent antiviral activity against VV by (1) direct antiviral effects against VV; and (2) stimulating the expression of endogenous AMPs with known antiviral activity against VV. In addition, we show that a topical application of CSA-13 penetrates the skin and reduces subsequent satellite lesion formation. This suggests that treatment with CSA-13 may be an intervention for individuals with a disseminated VV skin infection.


Subject(s)
Antiviral Agents/pharmacology , Dermatitis/drug therapy , Dermatitis/virology , Steroids/pharmacology , Vaccinia virus/drug effects , Vaccinia/drug therapy , Animals , Antiviral Agents/chemistry , Chlorocebus aethiops , Dermatitis/immunology , Humans , Keratinocytes/cytology , Keratinocytes/immunology , Keratinocytes/virology , Kidney/cytology , Mice , Mice, Hairless , Mice, SCID , Skin/virology , Steroids/chemistry , Vaccinia/immunology , Vaccinia virus/immunology , Vero Cells , Viral Envelope Proteins/immunology
4.
Acc Chem Res ; 41(10): 1233-40, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18616297

ABSTRACT

The prevalence of drug-resistant bacteria drives the quest for new antimicrobials, including those that are not expected to readily engender resistance. One option is to mimic Nature's most ubiquitous means of controlling bacterial growth, antimicrobial peptides, which have evolved over eons. In general, bacteria remain susceptible to these peptides. Human antimicrobial peptides play a central role in innate immunity, and deficiencies in these peptides have been tied to increased rates of infection. However, clinical use of antimicrobial peptides is hampered by issues of cost and stability. The development of nonpeptide mimics of antimicrobial peptides may provide the best of both worlds: a means of using the same mechanism chosen by Nature to control bacterial growth without the problems associated with peptide therapeutics. The ceragenins were developed to mimic the cationic, facially amphiphilic structures of most antimicrobial peptides. These compounds reproduce the required morphology using a bile-acid scaffolding and appended amine groups. The resulting compounds are actively bactericidal against both gram-positive and gram-negative organisms, including drug-resistant bacteria. This antimicrobial activity originates from selective association of the ceragenins with negatively charged bacterial membrane components. Association has been studied with synthetic models of bacterial membrane components, with bacterial lipopolysaccharide, with vesicles derived from bacterial phospholipids, and with whole cells. Comparisons of the antimicrobial activities of ceragenins and representative antimicrobial peptides suggest that these classes of compounds share a mechanism of action. Rapid membrane depolarization is caused by both classes as well as blebbing of bacterial membranes. Bacteria express the same genes in response to both classes of compounds. On the basis of the antibacterial activities of ceragenins and preliminary in vivo studies, we expect these compounds to find use in augmenting or replacing antimicrobial peptides in treating human disease.


Subject(s)
Anti-Bacterial Agents/chemistry , Biomimetic Materials/chemistry , Cholic Acid/chemistry , Peptides/chemistry , Steroids/chemistry , Animals , Anti-Bacterial Agents/pharmacology , Biomimetic Materials/pharmacology , Cell Membrane/metabolism , Drug Design , Escherichia coli/ultrastructure , Humans , Microbial Viability/drug effects , Micrococcus luteus/drug effects , Microscopy, Electron, Transmission , Molecular Sequence Data , Molecular Structure , NF-kappa B/metabolism , Peptides/pharmacology , Protein Transport , Staphylococcus aureus/drug effects , Steroids/pharmacology
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