Anti-Leishmanial Activity of Novel Homo- and Heteroleptic Bismuth(III) Thiocarboxylates

2013 ◽  
Vol 66 (10) ◽  
pp. 1297 ◽  
Author(s):  
Philip C. Andrews ◽  
Peter C. Junk ◽  
Lukasz Kedzierski ◽  
Roshani M. Peiris
Keyword(s):  
Mammalian Cells ◽  
Leishmania Major ◽  
Lone Pair ◽  
Phenyl Group ◽  
Distorted Octahedral Geometry ◽  
X Ray Crystallography ◽  
Highly Active ◽  
Thiobenzoic Acid ◽  
High Concentrations

Two new thiocarboxylic acids, p-bromothiobenzoic BTA and thionaphthoic acid TNA, and five new homo- and heteroleptic bismuth(iii) compounds derived from thiocarboxylic acids: [Bi{S(C=O)C6H4Br}3] 1, [PhBi{S(C=O)C6H4Br}2] 2, [Bi{S(C=O)C10H7}3] 3, [PhBi{S(C=O)C10H7}2] 4, and [Ph2Bi{S(C=O)C10H7}] 5 were synthesised and fully characterised. The solid-state structure of complex [PhBi{S(C=O)C6H4Br}2] 2 was confirmed by X-ray crystallography. In complex 2, the two thiocarboxylate ligands are coordinated to the bismuth(iii) centre in a didentate fashion, forming a distorted octahedral geometry in which the phenyl group and the lone pair are oriented axial to the plane formed by the two thiocarboxylate ligands. Long-range Bi–S interactions (3.54 Å) link these monomeric units to form a one-dimensional polymer. These compounds, in addition to six previously synthesised complexes: [Bi{SC(=O)C6H5}3] 6, [PhBi{SC(=O)C6H5}2] 7, [Ph2Bi{SC(=O)C6H5}] 8, [Bi{SC(=O)C6H4NO2}3] 9, [PhBi{SC(=O)C6H4NO2}2] 10, and [PhBi{SC(=O)C6H4SO3}] 11, and the thiocarboxylic acids themselves, were assessed for their in vitro activity against Leishmania major promastigotes, and for general toxicity against human fibroblast cells. The thiocarboxylic acids, with the exception of thiobenzoic acid and sulfothiobenzoic acid, were toxic to both L. major parasites and the mammalian cells at high concentrations of 50–100 μM. The bismuth(iii) thiocarboxylate derivatives proved to be more active than the corresponding acids. Among these, the heteroleptic phenyl-substituted bismuth(iii) complexes 2, 4, 5, and 7 were highly active, showing IC50 (half maximal inhibitory concentration) values ranging from 0.39 to 4.69 μM, and a clear ligand dependence on activity.

scholarly journals Acylhydrazones as Antifungal Agents Targeting the Synthesis of Fungal Sphingolipids

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Cristina Lazzarini ◽  
Krupanandan Haranahalli ◽  
Robert Rieger ◽  
Hari Krishna Ananthula ◽  
Pankaj B. Desai ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Fungal Resistance ◽  
Content Type ◽  
Highly Active ◽  
Pharmacokinetic Properties ◽  
Pass Through

ABSTRACTThe incidence of invasive fungal infections has risen dramatically in recent decades. Current antifungal drugs are either toxic, likely to interact with other drugs, have a narrow spectrum of activity, or induce fungal resistance. Hence, there is a great need for new antifungals, possibly with novel mechanisms of action. Previously our group reported an acylhydrazone called BHBM that targeted the sphingolipid pathway and showed strong antifungal activity against several fungi. In this study, we screened 19 derivatives of BHBM. Three out of 19 derivatives were highly active againstCryptococcus neoformansin vitroand had low toxicity in mammalian cells. In particular, one of them, called D13, had a high selectivity index and showed better activity in an animal model of cryptococcosis, candidiasis, and pulmonary aspergillosis. D13 also displayed suitable pharmacokinetic properties and was able to pass through the blood-brain barrier. These results suggest that acylhydrazones are promising molecules for the research and development of new antifungal agents.

Attachment of Salmonella to mammalian cells in vitro

1983 ◽  
Vol 29 (12) ◽  
pp. 1731-1735 ◽  
Author(s):  
Clifford S. Mintz ◽  
Dean O. Cliver ◽  
R. H. Deibel
Keyword(s):  
Cell Lines ◽  
Mammalian Cells ◽  
Culture Cell ◽  
Intestinal Cell ◽  
Tissue Culture Cell ◽  
Bacterial Cells ◽  
Intestinal Cell Line ◽  
Hela Cell Lines ◽  
High Concentrations

The attachment of Salmonella typhimurium strain PHL67342 to several mammalian tissue culture cell lines was investigated. Strain PHL67342 failed to attach in significant numbers to the Buffalo green monkey (BGM), swine testicular (ST), and HeLa cell lines. Significant attachment was observed with the Henle intestinal cell line. Log-phase cells of strain PHL67342 attached in greatest numbers to the Henle cells after 45 min of incubation at 37 °C. Attachment to the Henle cells was not affected by D-mannose or D-galactose, but was markedly inhibited by high concentrations of alpha-methyl-D-mannoside. Also, Salmonella lipopolysaccharide had no effect on the attachment of strain PHL67342 to the Henle cells. Fimbriae were not detected on the bacterial cells used in the adherence experiments. These results suggest that some bacterial factor(s) other than fimbriae and lipopolysaccharide mediate the attachment of strain PHL67342 to the Henle cells.

scholarly journals Zinc(II)-Dipicolylamine Coordination Complexes as Targeting and Chemotherapeutic Agents for Leishmania major

2016 ◽  
Vol 60 (5) ◽  
pp. 2932-2940 ◽  
Author(s):  
Douglas R. Rice ◽  
Paola Vacchina ◽  
Brianna Norris-Mullins ◽  
Miguel A. Morales ◽  
Bradley D. Smith
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Mammalian Cells ◽  
Leishmania Major ◽  
Parasite Burden ◽  
Coordination Complexes ◽  
Chemotherapeutic Agents ◽  
Selective Toxicity ◽  
Content Type

ABSTRACTCutaneous leishmaniasis is a neglected tropical disease that causes painful lesions and severe disfigurement. Modern treatment relies on a few chemotherapeutics with serious limitations, and there is a need for more effective alternatives. This study describes the selective targeting of zinc(II)-dipicolylamine (ZnDPA) coordination complexes towardLeishmania major, one of the species responsible for cutaneous leishmaniasis. Fluorescence microscopy ofL. majorpromastigotes treated with a fluorescently labeled ZnDPA probe indicated rapid accumulation of the probe within the axenic promastigote cytosol. The antileishmanial activities of eight ZnDPA complexes were measured using anin vitroassay. All tested complexes exhibited selective toxicity againstL. majoraxenic promastigotes, with 50% effective concentration values in the range of 12.7 to 0.3 μM. Similar toxicity was observed against intracellular amastigotes, but there was almost no effect on the viability of mammalian cells, including mouse peritoneal macrophages.In vivotreatment efficacy studies used fluorescence imaging to noninvasively monitor changes in the red fluorescence produced by an infection of mCherry-L. majorin a mouse model. A ZnDPA treatment regimen reduced the parasite burden nearly as well as the reference care agent, potassium antimony(III) tartrate, and with less necrosis in the local host tissue. The results demonstrate that ZnDPA coordination complexes are a promising new class of antileishmanial agents with potential for clinical translation.

scholarly journals Inhibition of Fumarate Reductase inLeishmania major and L. donovani by Chalcones

2001 ◽  
Vol 45 (7) ◽  
pp. 2023-2029 ◽  
Author(s):  
Ming Chen ◽  
Lin Zhai ◽  
Søren Brøgger Christensen ◽  
Thor G. Theander ◽  
Arsalan Kharazmi
Keyword(s):  
Respiratory Chain ◽  
Mammalian Cells ◽  
Leishmania Major ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Fumarate Reductase ◽  
Peripheral Blood Mononuclear ◽  
Licochalcone A

ABSTRACT Our previous studies have shown that chalcones exhibit potent antileishmanial and antimalarial activities in vitro and in vivo. Preliminary studies showed that these compounds destroyed the ultrastructure of Leishmania parasite mitochondria and inhibited the respiration and the activity of mitochondrial dehydrogenases of Leishmania parasites. The present study was designed to further investigate the mechanism of action of chalcones, focusing on the parasite respiratory chain. The data show that licochalcone A inhibited the activity of fumarate reductase (FRD) in the permeabilized Leishmania major promastigote and in the parasite mitochondria, and it also inhibited solubilized FRD and a purified FRD from L. donovani. Two other chalcones, 2,4-dimethoxy-4′-allyloxychalcone (24m4ac) and 2,4-dimethoxy-4′-butoxychalcone (24mbc), also exhibited inhibitory effects on the activity of solubilized FRD in L. majorpromastigotes. Although licochalcone A inhibited the activities of succinate dehydrogenase (SDH), NADH dehydrogenase (NDH), and succinate- and NADH-cytochrome c reductases in the parasite mitochondria, the 50% inhibitory concentrations (IC50) of licochalcone A for these enzymes were at least 20 times higher than that for FRD. The IC50 of licochalcone A for SDH and NDH in human peripheral blood mononuclear cells were at least 70 times higher than that for FRD. These findings indicate that FRD, one of the enzymes of the parasite respiratory chain, might be the specific target for the chalcones tested. Since FRD exists in the Leishmaniaparasite and does not exist in mammalian cells, it could be an excellent target for antiprotozoal drugs.

scholarly journals Purification and properties of an esterase from organophosphate-resistant strain of the mosquito Culex quinquefasciatus

1990 ◽  
Vol 266 (1) ◽  
pp. 83-90 ◽  
Author(s):  
A T Merryweather ◽  
J M Crampton ◽  
H Townson
Keyword(s):  
Culex Quinquefasciatus ◽  
Resistant Strain ◽  
Gel Electrophoresis ◽  
Polyacrylamide Gel Electrophoresis ◽  
Starch Gel Electrophoresis ◽  
Post Translational Modification ◽  
Highly Active ◽  
High Concentrations ◽  
Starch Gels

Organophosphate-resistant and -susceptible strains of Culex quinquefasciatus (mosquito) have been compared on the basis of their esterase activities. The homozygous resistant strain (Dar) shows two highly active esterases after starch-gel electrophoresis, of Rm 0.2 and 0.4, which are absent from susceptible strains (Apo, Mon), and which previous selection studies have shown to be inseparable from organophosphate resistance. After SDS/polyacrylamide-gel electrophoresis and silver staining of total C. quinquefasciatus proteins, a 62 kDa band is observed in strain Dar at high concentrations, and in susceptible strains in trace amounts. After Western blotting, this 62 kDa protein is recognized by antisera raised against the two esterases eluted from starch gels. After chromatofocusing of Dar proteins, the 62 kDa protein is seen to be associated with esterase activity, and of a similar pI to that observed for esterases after isoelectric focusing. Post-translational modification is not required for recognition of the 62 kDa putative esterase, since the protein is immunoprecipitated by the anti-esterase serum from products of translation of Dar mRNA in vitro.

scholarly journals Mammalian Casein Kinase 1α and Its Leishmanial Ortholog Regulate Stability of IFNAR1 and Type I Interferon Signaling

2009 ◽  
Vol 29 (24) ◽  
pp. 6401-6412 ◽  
Author(s):  
Jianghuai Liu ◽  
Lucas P. Carvalho ◽  
Sabyasachi Bhattacharya ◽  
Christopher J. Carbone ◽  
K. G. Suresh Kumar ◽  
...  
Keyword(s):  
Er Stress ◽  
Mammalian Cells ◽  
Leishmania Major ◽  
Type I Interferon ◽  
Casein Kinase ◽  
Type I ◽  
Bona Fide ◽  
Activity Dependent

ABSTRACT Phosphorylation of the degron of the IFNAR1 chain of the type I interferon (IFN) receptor triggers ubiquitination and degradation of this receptor and, therefore, plays a crucial role in negative regulation of IFN-α/β signaling. Besides the IFN-stimulated and Jak activity-dependent pathways, a basal ligand-independent phosphorylation of IFNAR1 has been described and implicated in downregulating IFNAR1 in response to virus-induced endoplasmic reticulum (ER) stress. Here we report purification and characterization of casein kinase 1α (CK1α) as a bona fide major IFNAR1 kinase that confers basal turnover of IFNAR1 and cooperates with ER stress stimuli to mediate phosphorylation-dependent degradation of IFNAR1. Activity of CK1α was required for phosphorylation and downregulation of IFNAR1 in response to ER stress and viral infection. While many forms of CK1 were capable of phosphorylating IFNAR1 in vitro, human CK1α and L-CK1 produced by the protozoan Leishmania major were also capable of increasing IFNAR1 degron phosphorylation in cells. Expression of leishmania CK1 in mammalian cells stimulated the phosphorylation-dependent downregulation of IFNAR1 and attenuated its signaling. Infection of mammalian cells with L. major modestly decreased IFNAR1 levels and attenuated cellular responses to IFN-α in vitro. We propose a role for mammalian and parasite CK1 enzymes in regulating IFNAR1 stability and type I IFN signaling.

scholarly journals Killing of Trypanozoon Parasites by the Equine Cathelicidin eCATH1

2016 ◽  
Vol 60 (5) ◽  
pp. 2610-2619 ◽  
Author(s):  
S. Cauchard ◽  
N. Van Reet ◽  
P. Büscher ◽  
D. Goux ◽  
J. Grötzinger ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Trypanosoma Evansi ◽  
Host Defense Peptides ◽  
Content Type ◽  
Sytox Green ◽  
Highly Active ◽  
Transmission Electron ◽  
Mitochondrial Alteration ◽  
Plasma Membrane Permeabilization

ABSTRACTTrypanozoonparasites infect both humans, causing sleeping sickness, and animals, causing nagana, surra, and dourine. Control of nagana and surra depends to a great extent on chemotherapy. However, drug resistance to several of the front-line drugs is rising. Furthermore, there is no official treatment for dourine. Therefore, there is an urgent need to develop antiparasitic agents with novel modes of action. Host defense peptides have recently gained attention as promising candidates. We have previously reported that one such peptide, the equine antimicrobial peptide eCATH1, is highly active against equine Gram-positive and Gram-negative bacteria, without cytotoxicity against mammalian cells at bacteriolytic concentrations. In the present study, we show that eCATH1 exhibits anin vitro50% inhibitory concentration (IC50) of 9.5 μM againstTrypanosoma brucei brucei,Trypanosoma evansi, andTrypanosoma equiperdum. Its trypanocidal mechanism involves plasma membrane permeabilization and mitochondrial alteration based on the following data: (i) eCATH1 induces the rapid influx of the vital dye SYTOX Green; (ii) it rapidly disrupts mitochondrial membrane potential, as revealed by immunofluorescence microscopy using the fluorescent dye rhodamine 123; (iii) it severely damages the membrane and intracellular structures of the parasites as early as 15 min after exposure at 9.5 μM and 5 min after exposure at higher concentrations (19 μM), as evidenced by scanning and transmission electron microscopy. We also demonstrate that administration of eCATH1 at a dose of 10 mg/kg toT. equiperdum-infected mice delays mortality. Taken together, our findings suggest that eCATH1 is an interesting template for the development of novel therapeutic agents in the treatment of trypanosome infections.

scholarly journals High-level expression and purification of a recombinant human erythropoietin produced using a baculovirus vector

Blood ◽  
1989 ◽  
Vol 74 (2) ◽  
pp. 652-657
Author(s):  
FW Quelle ◽  
LF Caslake ◽  
RE Burkert ◽  
DM Wojchowski
Keyword(s):  
Mammalian Cells ◽  
Recombinant Human Erythropoietin ◽  
Insect Cell Line ◽  
Recombinant Baculovirus ◽  
Cell Surface Receptor ◽  
High Level Expression ◽  
Human Erythropoietin ◽  
Highly Active ◽  
High Level

Conditions presently have been established for the high-level expression and simplified purification of recombinant human erythropoietin produced in Spodoptera frugiperda cells. Expression, as mediated by infection with a recombinant baculovirus, was accomplished in suspension culture using reduced levels of serum and media supplements experimentally determined to provide optimum levels of factor production (500,000 U/L). Purification of this recombinant human erythropoietin to virtual homogeneity (greater than or equal to 99%) was accomplished via a simple three-step procedure involving isocratic elution from DEAE-Sephacel, reverse-phase high performance liquid chromatography (HPLC) on a C4 medium, and the single-step elution of purified hormone from concanavalin A agarose. Overall, an 890-fold purification was accomplished with a recovery of 80% as assayed in vitro. Biologically, this purified erythropoietin is highly active, possessing a specific activity in vitro of 200,000 U/mg protein. Chemically, this erythropoietin (molecular weight [mol wt] 26,200) appears exceptionally uniform in its oligosaccharide constitution (30%) as contrasted with heterogeneously glycosylated erythropoietins derived from mammalian cells (mol wt 30,000 to 38,000; 40% to 50% complex-type oligosaccharide). Thus, human erythropoietin as presently produced in an insect cell line comprises not only an abundant source of highly active, readily purified hormone for studies of its mechanism of action and cell surface receptor, but also represents a uniquely homogeneous form that should prove advantageous for direct structural analyses.

scholarly journals Influence of Different Peritoneal Dialysis Fluids on theIn VitroActivity of Cefepime, Ciprofloxacin, Ertapenem, Meropenem and Tobramycin againstEscherichia Coli

2016 ◽  
Vol 36 (6) ◽  
pp. 662-668 ◽  
Author(s):  
Manuel Kussmann ◽  
Linda Schuster ◽  
Sarah Wrenger ◽  
Petra Pichler ◽  
Gottfried Reznicek ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Peritoneal Dialysis ◽  
Antimicrobial Agents ◽  
Highly Active ◽  
Microbiological Outcome ◽  
Mueller Hinton ◽  
Baxter Healthcare ◽  
High Concentrations ◽  
The Impact

BackgroundPeritonitis is a major problem among patients on peritoneal dialysis (PD). The influence of diverse PD fluids on the activity of frequently used antibiotics has been insufficiently investigated. Thus, the present study set out to investigate the impact of different PD fluids on the activity of cefepime, ciprofloxacin, ertapenem, meropenem, and tobramycin against Escherichia coli.MethodsTime-kill curves in 4 different PD fluids (Dianeal PDG4, Extraneal, Nutrineal PD4 and Physioneal 40, all Baxter Healthcare Corp., Deerfield, IL, USA) were performed over 24 hours with 4 different concentrations (1 x minimum inhibitory concentration [MIC], 4 x MIC, 8 x MIC, 30 x MIC) of each antibiotic evaluated and without antibiotics as control. Cation-adjusted Mueller Hinton broth (CA-MHB) was used as comparator solution.ResultsIn all PD fluids investigated, bacterial growth and antimicrobial activity of all antibiotics tested was significantly reduced compared with the CA-MHB comparator solution. Except at high concentrations of 30 x MIC, cefepime, ertapenem and meropenem demonstrated a strongly reduced activity in all PD fluids investigated. Ciprofloxacin and tobramycin were highly active and bactericidal in all PD fluids and demonstrated dose-dependent activity.ConclusionThe antimicrobial activity of cefepime, ertapenem and meropenem is limited or even nullified in certain PD fluids in vitro, whereas ciprofloxacin and tobramycin show excellent activity. The choice of PD fluids can impact the activity of antimicrobial agents and might influence microbiological outcome. Further studies are required to verify the clinical relevance of our findings.

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