scholarly journals Trifluoromethionine, a Prodrug Designed against Methionine γ-Lyase-Containing Pathogens, Has Efficacy In Vitro and In Vivo against Trichomonas vaginalis

2001 ◽  
Vol 45 (6) ◽  
pp. 1743-1745 ◽  
Author(s):  
Graham H. Coombs ◽  
Jeremy C. Mottram
Keyword(s):  
Drug Target ◽  
Trichomonas Vaginalis ◽  
Anaerobic Bacteria ◽  
Protozoan Parasite ◽  
Chemotherapeutic Agents ◽  
Single Step ◽  
Lesion Formation ◽  
Highly Active

ABSTRACT Methionine γ-lyase, the enzyme which catalyzes the single-step conversion of methionine to α-ketobutyrate, ammonia, and methanethiol, is highly active in many anaerobic pathogenic microorganisms but has no counterpart in mammals. This study tested the hypothesis that this pathogen-specific enzyme can be exploited as a drug target by prodrugs that are exclusively activated by it. Trifluoromethionine was confirmed as such a prodrug and shown to be highly toxic in vitro to the anaerobic protozoan parasiteTrichomonas vaginalis, to anaerobic bacteria containing methionine γ-lyase, and to Escherichia coli expressing the trichomonad gene. The compound also has exceptional activity against the parasite growing in vivo, with a single dose preventing lesion formation in five of the six mice challenged. These findings suggest that trifluoromethionine represents a lead compound for a novel class of anti-infective drugs with potential as chemotherapeutic agents against a range of prokaryotic and eukaryotic anaerobic pathogens.

scholarly journals Thermal behavior and biological activity of [Co2(Cl)2 tpmc](BF4)2 complex

2021 ◽  
Vol 62 (4) ◽  
pp. 291-296
Author(s):  
Slađana Tanasković ◽  
Mirjana Antonijević-Nikolić ◽  
Branka Dražić
Keyword(s):  
Biological Activity ◽  
Human Cancer ◽  
Chair Conformation ◽  
Single Step ◽  
Moderate Activity ◽  
Human Cancer Cell Lines ◽  
Highly Active ◽  
Dta Analysis

A large number of interesting Co (II) complexes with macrocyclicligands have been synthesized and the recognition of its complexes as important bioactive compounds in vitro and in vivo has aroused growing interest in these agents as potential drugs for therapeutic use in various diseases. Numerous available information on their bioinorganic properties and mode of action in several biological systems, combined with the new possibilities imposed by the development of medical chemistry, opens space for the development of a new generation of highly active drugs with minimized side effects which could add significantly to the current clinical research and practice. In this paper we attempt to present some properties of the earlier isolated the first Co(II)tpmc complex for which crystal structure confirmed chair conformation of macrocycle. Complex with formula (Co2(Cl)2tpmc)(BF4)2 (tpmc = N,N`,N``,N```tetrakis(2-pyridylmethyl)-1,4,8,11 - tetraazacyclotetradecane), was studied on thermal behaviour and biological activity. TG-DTA analysis indicates that complex decomposition in a single step in the range of 365 -435 °C. Investigated cytotoxic activity against two human cancer cell lines: HeLa (human cervix adenocarcinoma) and K562 (human myelogenous leukaemia). Complex was also preliminary assayed in vitro toward bacteria, fungi and mould together with the starting material for the synthesis (ligands, simple salts and solvents) as test substances. Investigated complex showed a moderate activity against strains of bacteria and were inactive against the tested fungi and mould. Minimal inhibitory concentration suppressing the visible growth of bacteria was determined. Biological investigations show the complex has significant cytotoxic potential.

scholarly journals In Vitro and In Vivo Antimicrobial Activities of T-3811ME, a Novel Des-F(6)-Quinolone

1999 ◽  
Vol 43 (5) ◽  
pp. 1077-1084 ◽  
Author(s):  
Masahiro Takahata ◽  
Junichi Mitsuyama ◽  
Yoshiko Yamashiro ◽  
Minoru Yonezawa ◽  
Harumi Araki ◽  
...  
Keyword(s):  
Anaerobic Bacteria ◽  
Active Agent ◽  
Systemic Infection ◽  
Antimicrobial Activities ◽  
Gram Positive ◽  
Highly Active ◽  
Wide Range ◽  
Gram Positive Cocci

ABSTRACT The in vitro and in vivo activities of T-3811ME, a novel des-F(6)-quinolone, were evaluated in comparison with those of some fluoroquinolones, including a newly developed one, trovafloxacin. T-3811, a free base of T-3811ME, showed a wide range of antimicrobial spectra, including activities against Chlamydia trachomatis, Mycoplasma pneumoniae, andMycobacterium tuberculosis. In particular, T-3811 exhibited potent activity against various gram-positive cocci, with MICs at which 90% of the isolates are inhibited (MIC90s) of 0.025 to 6.25 μg/ml. T-3811 was the most active agent against methicillin-resistant Staphylococcus aureus and streptococci, including penicillin-resistant Streptococcus pneumoniae (PRSP). T-3811 also showed potent activity against quinolone-resistant gram-positive cocci with GyrA and ParC (GrlA) mutations. The activity of T-3811 against members of the familyEnterobacteriaceae and nonfermentative gram-negative rods was comparable to that of trovafloxacin. In common with other fluoroquinolones, T-3811 was highly active against Haemophilus influenzae, Moraxella catarrhalis, andLegionella sp., with MIC90s of 0.0125 to 0.1 μg/ml. T-3811 showed a potent activity against anaerobic bacteria, such as Bacteroides fragilis and Clostridium difficile. T-3811 was the most active agent against C. trachomatis (MIC, 0.008 μg/ml) and M. pneumoniae(MIC90, 0.0313 μg/ml). The activity of T-3811 againstM. tuberculosis (MIC90, 0.0625 μg/ml) was potent and superior to that of trovafloxacin. In experimental systemic infection with a GrlA mutant of S. aureus and experimental pneumonia with PRSP in mice, T-3811ME showed excellent therapeutic efficacy in oral and subcutaneous administrations.

scholarly journals Phytochemicals and Potential Therapeutic Targets on Toxoplasma gondii Parasite

2020 ◽  
Vol 20 (9) ◽  
pp. 739-753
Author(s):  
Sharif Alhassan Abdullahi ◽  
Ngah Zasmy Unyah ◽  
Noshariza Nordin ◽  
Rusliza Basir ◽  
Wana Mohammed Nasir ◽  
...  
Keyword(s):  
Drug Target ◽  
Relevant Literature ◽  
Chemotherapeutic Agents ◽  
Potential Drug ◽  
Natural Sources ◽  
Drug Candidates ◽  
Target Sites ◽  
Phytochemical Compounds

Identification of drug target in protozoan T. gondii is an important step in the development of chemotherapeutic agents. Likewise, exploring phytochemical compounds effective against the parasite can lead to the development of new drug agent that can be useful for prophylaxis and treatment of toxoplasmosis. In this review, we searched for the relevant literature on the herbs that were tested against T. gondii either in vitro or in vivo, as well as different phytochemicals and their potential activities on T. gondii. Potential activities of major phytochemicals, such as alkaloid, flavonoid, terpenoids and tannins on various target sites on T. gondii as well as other related parasites was discussed. It is believed that the phytochemicals from natural sources are potential drug candidates for the treatment of toxoplasmosis with little or no toxicity to humans.

Efficacy of Punica granatum extract on in vitro and in vivo control of Trichomonas vaginalis

Planta Medica ◽  
2011 ◽  
Vol 77 (12) ◽  
Author(s):  
GT El Sherbini ◽  
KM Ibrahim ◽  
ET El Sherbini ◽  
NM Abdel Hady ◽  
TA Morsy
Keyword(s):  
Trichomonas Vaginalis ◽  
Punica Granatum

scholarly journals Therapeutic Application of Brain-Specific Angiogenesis Inhibitor 1 for Cancer Therapy

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3562
Author(s):  
Mitra Nair ◽  
Chelsea Bolyard ◽  
Tae Jin Lee ◽  
Balveen Kaur ◽  
Ji Young Yoo
Keyword(s):  
Angiogenesis Inhibitor ◽  
Suppressor Gene ◽  
Chemotherapeutic Agents ◽  
Tumor Models ◽  
In Vivo Models ◽  
Herpes Simplex Viruses ◽  
Multiple Tumor ◽  
And Function

Brain-specific angiogenesis inhibitor 1 (BAI1/ADGRB1) is an adhesion G protein-coupled receptor that has been found to play key roles in phagocytosis, inflammation, synaptogenesis, the inhibition of angiogenesis, and myoblast fusion. As the name suggests, it is primarily expressed in the brain, with a high expression in the normal adult and developing brain. Additionally, its expression is reduced in brain cancers, such as glioblastoma (GBM) and peripheral cancers, suggesting that BAI1 is a tumor suppressor gene. Several investigators have demonstrated that the restoration of BAI1 expression in cancer cells results in reduced tumor growth and angiogenesis. Its expression has also been shown to be inversely correlated with tumor progression, neovascularization, and peri-tumoral brain edema. One method of restoring BAI1 expression is by using oncolytic virus (OV) therapy, a strategy which has been tested in various tumor models. Oncolytic herpes simplex viruses engineered to express the secreted fragment of BAI1, called Vasculostatin (Vstat120), have shown potent anti-tumor and anti-angiogenic effects in multiple tumor models. Combining Vstat120-expressing oHSVs with other chemotherapeutic agents has also shown to increase the overall anti-tumor efficacy in both in vitro and in vivo models. In the current review, we describe the structure and function of BAI1 and summarize its application in the context of cancer treatment.

scholarly journals Histone methyltransferase WHSC1 inhibits colorectal cancer cell apoptosis via targeting anti-apoptotic BCL2

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yu Wang ◽  
Liming Zhu ◽  
Mei Guo ◽  
Gang Sun ◽  
Kun Zhou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cell ◽  
Cell Apoptosis ◽  
B Cell Lymphoma ◽  
Histone Methyltransferase ◽  
Chemotherapeutic Agents ◽  
Cancer Cell Apoptosis ◽  
Active Transcription

AbstractWHSC1 is a histone methyltransferase that facilitates histone H3 lysine 36 dimethylation (H3K36me2), which is a permissive mark associated with active transcription. In this study, we revealed how WHSC1 regulates tumorigenesis and chemosensitivity of colorectal cancer (CRC). Our data showed that WHSC1 as well as H3K36me2 were highly expressed in clinical CRC samples, and high WHSC1 expression is associated with poorer prognosis in CRC patients. WHSC1 reduction promoted colon cancer cell apoptosis both in vivo and in vitro. We found that B cell lymphoma-2 (BCL2) expression, an anti-apoptotic protein, is markedly decreased in after WHSC1 depletion. Mechanistic characterization indicated that WHSC1 directly binds to the promoter region of BCL2 gene and regulate its H3K36 dimethylation level. What’s more, our study indicated that WHSC1 depletion promotes chemosensitivity in CRC cells. Together, our results suggested that WHSC1 and H3K36me2 modification might be optimal therapeutic targets to disrupt CRC progression and WHSC1-targeted therapy might potentially overcome the resistance of chemotherapeutic agents.

scholarly journals Characterization and selective inhibition of myristoyl-CoA:protein N-myristoyltransferase from Trypanosoma brucei and Leishmania major

2006 ◽  
Vol 396 (2) ◽  
pp. 277-285 ◽  
Author(s):  
Chrysoula Panethymitaki ◽  
Paul W. Bowyer ◽  
Helen P. Price ◽  
Robin J. Leatherbarrow ◽  
Katherine A. Brown ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Leishmania Major ◽  
Homo Sapiens ◽  
Selective Inhibition ◽  
Fungal Species ◽  
Chemotherapeutic Agents ◽  
Human Pathogens ◽  
Ic50 Values

The eukaryotic enzyme NMT (myristoyl-CoA:protein N-myristoyltransferase) has been characterized in a range of species from Saccharomyces cerevisiae to Homo sapiens. NMT is essential for viability in a number of human pathogens, including the fungi Candida albicans and Cryptococcus neoformans, and the parasitic protozoa Leishmania major and Trypanosoma brucei. We have purified the Leishmania and T. brucei NMTs as active recombinant proteins and carried out kinetic analyses with their essential fatty acid donor, myristoyl-CoA and specific peptide substrates. A number of inhibitory compounds that target NMT in fungal species have been tested against the parasite enzymes in vitro and against live parasites in vivo. Two of these compounds inhibit TbNMT with IC50 values of <1 μM and are also active against mammalian parasite stages, with ED50 (the effective dose that allows 50% cell growth) values of 16–66 μM and low toxicity to murine macrophages. These results suggest that targeting NMT could be a valid approach for the development of chemotherapeutic agents against infectious diseases including African sleeping sickness and Nagana.

Host oyster tissue extracts modulate in vitro protease expression and cellular differentiation in the protozoan parasite, Perkinsus marinus

Parasitology ◽  
2003 ◽  
Vol 126 (4) ◽  
pp. 293-302 ◽  
Author(s):  
E. A. MACINTYRE ◽  
C. G. EARNHART ◽  
S. L. KAATTARI
Keyword(s):  
Serine Proteases ◽  
Protozoan Parasite ◽  
Eastern Oyster ◽  
Defined Medium ◽  
Tissue Homogenate ◽  
Oyster Tissue ◽  
Perkinsus Marinus ◽  
Tissue Extracts

Perkinsus marinus is responsible for a chronic disease (Dermo) of the Eastern oyster, Crassostrea virginica. In order to simulate the in vivo environment more closely, a chemically defined medium (JL-ODRP-3) was supplemented with tissue homogenate extracts or plasma from oysters possessing varying degrees of susceptibility to P. marinus infection. In media supplemented with extracts from highly susceptible oysters (C. virginica), P. marinus cells secreted elevated amounts of a set of low molecular weight serine proteases (LMP: 30–45 kDa) as assessed by enhanced digestion within gelatin-substrate SDS–PAGE gels. Oyster species of low susceptibility (C. gigas and C. ariakensis) did not exhibit this ability to upregulate P. marinus LMP expression. Oyster extract supplementation also led to pronounced changes in P. marinus cellular morphology, such that the cells were comparable to those observed within naturally infected oysters.

In-vitro and in-vivo potency of five new fluoroquinolones against anaerobic bacteria

1986 ◽  
Vol 18 (6) ◽  
pp. 693-701 ◽  
Author(s):  
Prabhavathi B. Fernandes ◽  
Nathan Shipkowitz ◽  
Robert R. Bower ◽  
Kenneth P. Jarvis ◽  
Jonina Weisz ◽  
...  
Keyword(s):  
Anaerobic Bacteria

scholarly journals Ex VivoMaturation Assay for Testing Antimalarial Sensitivity of Rodent Malaria Parasites

2016 ◽  
Vol 60 (11) ◽  
pp. 6859-6866 ◽  
Author(s):  
Zi Wei Chang ◽  
Benoit Malleret ◽  
Bruce Russell ◽  
Laurent Rénia ◽  
Carla Claser
Keyword(s):  
Ex Vivo ◽  
Single Step ◽  
Parasite Development ◽  
Ring Stage ◽  
Malaria Parasites ◽  
Rodent Malaria ◽  
Content Type ◽  
Parasite Biology

ABSTRACTEx vivoassay systems provide a powerful approach to studying human malaria parasite biology and to testing antimalarials. For rodent malaria parasites, short-termin vitroculture andex vivoantimalarial susceptibility assays are relatively cumbersome, relying onin vivopassage for synchronization, since ring-stage parasites are an essential starting material. Here, we describe a new approach based on the enrichment of ring-stagePlasmodium berghei,P. yoelii, andP. vinckei vinckeiusing a single-step Percoll gradient. Importantly, we demonstrate that the enriched ring-stage parasites develop synchronously regardless of the parasite strain or species used. Using a flow cytometry assay with Hoechst and ethidium or MitoTracker dye, we show that parasite development is easily and rapidly monitored. Finally, we demonstrate that this approach can be used to screen antimalarial drugs.

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