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Ursolic, oleanolic and betulinic acids: antibacterial spectra and selectivity indexes.

ETHNOPHARMACOLOGICAL RELEVANCE Ursolic acid (UA), oleanolic acid (OA) and betulinic acid (BA), three hydroxyl pentacyclic triterpenoic acids (HPTAs) naturally found in a large variety of vegetarian foods, medicinal herbs and plants have been investigated for antibacterial activity. AIM OF THE STUDY To determine the antibacterial activity of UA, OA and BA, as well as the toxic impact on eukaryotic cells. MATERIALS AND METHODS Minimum inhibitory concentrations were determined against five reference strains (Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 25923 & ATCC 29213, Enterococcus faecalis ATCC 29212 and Pseudomonas aeruginosa ATCC 27853), as well as five antibiotic-resistant clinical isolates. Toxicity was evaluated against MRC-5 and HaCaT cell lines. RESULTS No antibacterial activity was observed for BA; while OA and more particularly UA, did show a moderate to good antibacterial activity, but limited to Gram-positive bacteria. Nevertheless, OA and UA were devoid of antibacterial activities against clinical isolates. Moreover, viability and cytotoxic assays demonstrated that the three compounds induced a significant cytotoxicity. CONCLUSIONS Despite of a relative similar chemical structure; UA, OA and BA harboured different antibacterial activities, with more significant ones for UA. However, considering both viability and toxicity values, these compounds seem to have a significant impact on eukaryotic cell viability.

Cationic compounds with activity against multidrug-resistant bacteria: interest of a new compound compared with two older antiseptics, hexamidine and chlorhexidine

Use of antiseptics and disinfectants is essential in infection control practices in hospital and other healthcare settings. In this study, the in vitro activity of a new promising compound, para-guanidinoethylcalix[4]arene (Cx1), has been evaluated in comparison with hexamidine (HX) and chlorhexidine (CHX), two older cationic antiseptics. The MICs for 69 clinical isolates comprising methicillin-resistant Staphylococcus aureus, methicillin-sensitive S. aureus, coagulase-negative staphylococci (CoNS) (with or without mecA), vancomycin-resistant enterococci, Enterobacteriaceae producing various beta-lactamases and non-fermenting bacilli (Pseudomonas aeruginosa, Acinetobacter baumanii, Stenotrophomonas maltophilia) were determined. Cx1 showed similar activity against S. aureus, CoNS and Enterococcus spp., irrespective of the presence of mecA or van genes, or associated resistance genes, with very good activity against CoNS (MIC <1 mg/L). Variable activities were observed against Enterobacteriaceae; the MICs determined seemed to be dependent both on the genus (MICs of 2, 8 and 64 mg/L for Escherichia coli, Klebsiella pneumoniae and Yersinia enterocolitica, respectively) and on the resistance phenotype production of [Extended Spectrum beta-Lactase (ESBLs) or other beta-lactamases; overproduction of AmpC]. Poor activity was found against non-fermenting bacilli, irrespective of the resistance phenotype. CHX appeared to be the most active compound against all strains, with broad-spectrum and conserved activity against multidrug-resistant strains. HX showed a lower activity, essentially against Gram-positive strains. Consequently, the differences observed with respect to Cx1 suggest that they are certainly not the consequence of antibiotic resistance phenotypes, but rather the result of membrane composition modifications (e.g. of lipopolysaccharide), or of the presence of (activated) efflux-pumps. These results raise the possibility that Cx1 may be a potent new antibacterial agent of somewhat lower activity but significantly lower toxicity than CHX.

Complexation study and anticellular activity enhancement by doxorubicin-cyclodextrin complexes on a multidrug-resistant adenocarcinoma cell line

Ability of molecular complexes of [Doxorubicin (DX)-cyclodextrin (Cd)] to enhance the anticellular activity of antineoplastic drug Doxorubicin and to reverse its multidrug resistance has been investigated. A spectroscopic study of the alpha, beta, and gamma-[DX-Cds] complexes has been investigated in relation to their biological effects on a multidrug resistant (MDR) human rectal adenocarcinoma cell line (HRT-18). A ten fold enhancement of DX anticellular activity in presence of beta-cyclodextrin alone was detected.

Recognition ability and cytotoxicity of some oligosaccharidylsubstituted β-cyclodextrins

Summary— This paper reports a chemico‐enzymatic synthesis of β‐CD derivatives. The recognition properties of these derivativeswere tested using flocculating yeast and isolated lectins. It was observed that the substitution of β‐cyclodextrins with galactose end arms induces the better recognition by a cell‐linked galactose‐specific lectin. The physicochemical effects of the β‐CD derivatives on membranes were estimated using red blood cells and the effects on the viability of yeast and human rectal tumor cells were appreciated by measuring the mitochondrial deshydrogenase activity. The substitutions of the β‐CD ring by sugar antennae decrease the negative physicochemical effects of the β‐CD, ie their, hemolytic properties. However, these substitutions induce significant modifications of the biological properties of the molecules, particularly the cytotoxicity and the growth of eukaryotic cells.

Effective ribavirin concentration in mice brain using cyclodextrin as a drug carrier: Evaluation in a measles encephalitis model

Ribavirin (RBV) is a water-soluble synthetic nucleoside with broad spectrum antiviral properties, but it is ineffective against major viral encephalitis because of a failure to cross the blood-brain barrier (BBB). The antiviral activity of the complex ribavirin/alpha-cyclodextrin was previously demonstrated to be stronger than free ribavirin, in an in vivo model of measles virus (MV) encephalitis in mice. The role of cyclodextrin (CD) on ribavirin uptake into the brain needs to be defined. Ribavirin specific extraction from brain tissue was developed, based on a solid phase extraction. It was quantified by high performance liquid chromatography at different time points after intraperitoneal injection of single or multiple doses of free ribavirin or of the complex ribavirin/alpha-cyclodextrin. Whatever the tested dose (40 or 100mg/kg), the amount of ribavirin in the brain was significantly higher (p<0.001) when the drug was injected as a complex with alpha-cyclodextrin, in healthy or measles virus-infected mice.

In vitro antiviral efficacy of the ganciclovir complexed with β-cyclodextrin on human cytomegalovirus clinical strains

The toxicity of the compounds currently used in the treatment of human cytomegalovirus (HCMV) infections in immunocompromised hosts may force the treatment to be discontinued. The aim of this study was to improve the antiviral activity of ganciclovir (GCV), one the most widely used drug, by complexing it with beta-cyclodextrin. Cyclodextrins (cds) have the property to form inclusion complexes with a great number of molecules and to enhance bioavailability and biological properties of these molecules. In this study, we investigated the in vitro antiviral activity of complexed GCV against several strains of HCMV: AD169, a reference strain, RCL-1, a laboratory mutant resistant to GCV, and four clinical isolates. The complexed GCV was more effective than free GCV against all HCMV strains tested. Cds as carriers for antiviral drugs would represent a useful adjunct to classical treatment procedures. They may make it possible to administer lower doses, thus reducing the toxic side effects of the drugs.

Tetrazolium salts for MIC determination in microplates: why? Which salt to select? How?

We reported evaluation of a colorimetric MIC assessment for routine susceptibility testing of non-fastidious bacteria, with addition of growth indicators (INT and MTT). Our results made us postulate that the use of such indicators was unnecessary for MIC determination in routine microdilution method.

Effect of the complexation with cyclodextrins on the in vitro antiviral activity of ganciclovir against Human Cytomegalovirus

The toxicity of the molecules currently used in the treatment of human cytomegalovirus (HCMV) in immunocompromised hosts often causes interruption of the therapy. Cyclodextrins (Cds), oligosaccharides possessing a hydrophobic cavity, have the property of forming inclusion complexes with a great number of molecules, improving their bioavailability and their biological properties. In this study, we have tested the ability of three native Cds to improve the antiviral effect of ganciclovir (GCV) on two HCMV strains: AD169, a reference susceptible strain, and RC11, a GCV resistant strain. The efficacy of the GCV, expressed in IC50 values, showed no improvement in the presence of alpha-Cd, while the use of beta- and gamma-Cd improved by 6- and 4-fold, respectively, its antiviral activity tested on AD169 strain. The influence of beta- or gamma-Cd on GCV efficiency evaluated on RC11 strain showed a decrease of the IC50. Parallel NMR studies were undertaken in order to characterize formation of [GCV:Cd] complexes. The results showed that complexation between alpha- or gamma-Cd and GCV did not occur. In contrast, spectra proved that beta-Cd formed an inclusion complex with GCV. This complex was characterized in UV-Visible spectrophotometry and the influence of the beta-Cd on the GCV penetration in cells was measured. The use of Cds as carriers of antiviral drugs would be a good alternative to traditional treatment, because it may allow the administration of lower doses and so continuous treatment by reducing the toxic effects of drugs.

Antiseptic properties of two calix[4]arenes derivatives on the human coronavirus 229E

Abstract Facing the lack in specific antiviral treatment, it is necessary to develop new means of prevention. In the case of the Coronaviridae this family is now recognized as including potent human pathogens causing upper and lower respiratory tract infections as well as nosocomial ones. Within the purpose of developing new antiseptics molecules, the antiseptic virucidal activity of two calix[4]arene derivatives, the tetra-para-sulfonato-calix[4]arene (C[4]S) and the 1,3-bis(bithiazolyl)-tetra-para-sulfonato-calix[4]arene (C[4]S-BTZ) were evaluated toward the human coronavirus 229E (HCoV 229E). Comparing these results with some obtained previously with chlorhexidine and hexamidine, (i) these two calixarenes did not show any cytotoxicity contrary to chlorhexidine and hexamidine, (ii) C[4]S showed as did hexamidine, a very weak activity against HCoV 229E, and (iii) the C[4]S-BTZ showed a stronger activity than chlorhexidine, i.e. 2.7 and 1.4log10 reduction in viral titer after 5min of contact with 10−3 molL−1 solutions of C[4]S-BTZ and chlorhexidine, respectively. Thus, the C[4]S-BTZ appeared as a promising virucidal (antiseptic) molecule.

Susceptibility of Clinical Strains of Herpes simplex Virus to Three Nucleoside Analogues

The susceptibility of clinical isolates of herpes simplex virus 1 (HSV1) (58 strains) and 2 (HSV2) (17 strains) from the Centre Hospitalier et Universitaire de Nancy to three nucleoside analogues was compared by the dye uptake method. As expected, all strains of HSV2 were resistant to brovavir or sorivudine. Aciclovir and penciclovir activities were comparable; 2 strains of HSV1 were resistant to these two compounds. Four strains isolated from immunocompromised patients gave different results with brovavir as compared to aciclovir; resistance to aciclovir (1 strain of HSV1) did not correlate with resistance to brovavir (3 strains of HSV1). Following up antiviral susceptibility is of interest for the detection of resistant strains in immunocompromised patients receiving prophylactic aciclovir.