Download or read book Investigating the Cytostatic and Cytocidal Mechanisms of Quinoline Drug Resistance in Plasmodium Falciparum written by Alexander Patrick Gorka and published by . This book was released on 2013 with total page 626 pages. Available in PDF, EPUB and Kindle. Book excerpt: Collectively, this work provides additional insight into cytostatic and cytocidal quinoline drug pharmacology and assists development of new, efficacious drugs in the fight against resistance.

Download or read book Investigating Potential Mechanisms of Cytocidal Drug Resistance in Plasmodium Falciparum written by David Alejandro Gaviria and published by . This book was released on 2013 with total page 436 pages. Available in PDF, EPUB and Kindle. Book excerpt: By quantifying antimalarial cytocidal activities (measured as LD50s) and comparing them to cytostatic activities (measured as IC50s), Paguio et al., 2011 showed a clear difference between some drug activities at different drug levels. This work showed that fold-resistance ratios are dramatically different at cytostatic vs. cytocidal drug levels as are multidrug resistance (MDR) patterns and verapamil (VPL) chemoreversal. These observations provide a fertile ground for research in elucidating drug targets and mechanisms at cytocidal levels. Ghosh et al., 2012 elucidated an autophagy pathway involved in mitochondrial degradation in response to starvation in T. gondii, the organism most closely related to human malaria parasites outside of other Plasmodium species. Sequence analyses of the autophagy-related (Atg) proteins found in T. gondii reveal close homologues in P. falciparum. Atg protein homologues involved in every step of the canonical autophagy pathway were found. Vps34 (the catalytic subunit of the kinase complex responsible for phagophore nucleation) is highly homologous within conserved domains, though it is much larger due to repetitive sequences that exist between putative helical regions. Since chloroquine (CQ) is an established inhibitor of autophagy and autophagy appears to be a functional system in malaria parasites, I have investigated the function of this pathway in malaria parasites and any possible connections to CQ resistance (CQR). This work has produced important insights into the poorly understood role of Atg proteins in malaria parasites, their regulation, and signaling pathways. Importantly, the data contained in this work suggest a relationship between autophagy and resistance to CQ. Moreover, differences between CQ sensitive (CQS) and CQR parasites suggest that Ca2+ transients may also play a role in resistance.

Download or read book Analysis of Drug Resistance Mechanisms in Intact Plasmodium Falciparum infected Red Blood Cells written by Sarah Reiling and published by . This book was released on 2015 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Malaria is a major global health concern, with half of the world's population being at risk of infection. Among the Plasmodium species that infect humans, P. falciparum causes most fatalities. Chloroquine (CQ) was the drug of choice for decades and considered safe, affordable and easy-to-use until resistance emerged. However, the exact mechanism of CQ resistance is not known. CQ is suggested to accumulate in the parasite's digestive vacuole due to its weak base properties, where it exerts its antimalarial action. Several transporters are involved in intracellular distribution of antimalarial drugs. Among them are the P. falciparum chloroquine resistance transporter (PfCRT) and the P. falciparum multidrug resistance 1 transporter (PfMDR1). Both are located in the digestive vacuolar membrane but transport substrates in opposing directions. While PfCRT transports substrates out of the digestive vacuole (DV), PfMDR1 transports substrates into the DV. PfMDR1 contains five polymorphisms that are suggested to be involved in altered drug transport, although the exact role of each amino acid mutation remains unknown. To gain more insight into the transport functions of PfMDR1, variants with different mutation patterns were analyzed using the fluorescent substrate Fluo-4. We found a crucial role for asparagine (N) at residue 1042 in Fluo-4 transport, while substitution with aspartic acid (D) abolished all transport. In addition, we showed an association of the PfMDR1 N1042D mutation with increased mefloquine but decreased quinine sensitivity. Furthermore, competition studies of Fluo-4 with the antimalarial drugs chloroquine, mefloquine and quinine showed distinct transport inhibition patterns for parasites of different genetic background. This can be used as a tool to evaluate parasite susceptibility to antimalarial drugs.Next, we investigated the mechanism of resistance to CQ in more detail. We showed that parasite survival is higher in CQ-resistant strains compared to CQ-sensitive strains in the initial 10 hours after exposure to equally lethal CQ concentrations. Moreover, dark cytosolic structures appeared in CQ-sensitive strains that were later confirmed as hemozoin-containing compartments surrounded by a membrane bilayer. Leakage of hemozoin crystals out of the DV was ruled out since lysis of the digestive vacuolar membrane did not occur during that time frame. These data suggest that CQ resistance is not linked to reduced drug concentrations in the DV alone, and additional regulatory mechanisms in the parasite must play a crucial role during CQ exposure.To pursue these findings, a commercially available fluorescent tagged CQ analogue, LynxTagTM-CQ-GREEN (CQ-GREEN), was examined for its suitability in studying CQ transport and intracellular drug accumulation. While CQ-GREEN was half as effective in parasite killing of CQ-sensitive strains compared to unmodified CQ, no significant changes in parasite killing were observed in CQ-resistant strains. However, live cell imaging showed that CQ-GREEN accumulated in the parasite cytosol and not the DV. These results show for the first time a potential target for a CQ analogue outside the digestive vacuole. Moreover, intracellular CQGREEN uptake rates were reduced in CQ-resistant strains compared to CQ-sensitive strains. This, too, suggests that CQ-resistant strains must have evolved a regulatory mechanism to decrease intracellular CQ accumulation.The results presented in this thesis expand our understanding of substrate transport by PfMDR1. Furthermore, a novel phenotype was described for CQ-sensitive strains upon drug exposure that was not seen in CQ-resistant strains. These data suggest that altered regulatory mechanisms play a role in CQ resistance and are likely located in the parasite cytosol." --

Download or read book Mechanisms of Drug Resistance in Plasmodium Falciparum written by and published by . This book was released on 1994 with total page 69 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria continues as a major health threat throughout the tropical world and potential demand for antimalarials is higher than for any other medication yet the world faces a crisis--drug resistance is emerging and spreading faster than drugs are being developed and the flow in the pipeline of new drugs has all but stopped. This represents a particular threat to the US military. In a short time there may be parts of the world where no effective antimalarial drug is available. The recent emergence of multidrug resistant malaria parasites has intensified this problem. The goal of this work is to use a molecular genetic approach in the investigation of mechanisms of drug resistance and subsequently to use this information in the identification and development of new antimalarial drugs. These studies were initiated based on the observation that one mechanism of drug resistance in P. falciparum may be similar to multidrug resistance in cancer. During this work, we identified and fully characterized two mdr-like genes in P. falciparum, pfmdrl and pfmdr2 and have found an association with the amplification and over expression of one of these genes, pfmdrl with mefloquine resistance and multidrug resistant parasites both in laboratory derived and field isolated strains of Plasmodium falciparum. As a next step in this work, we have initiated the development methods of functional analysis which are critical both to developing and testing new chemotherapeutic interventions. Malaria, Drug resistance, Recombinant DNA, Tropical disease, Infectious disease.

Download or read book Physiology Directed Drug Discovery in Multidrug Resistant Plasmodium Falciparum written by Amila Chathuranga Siriwardana and published by . This book was released on 2017 with total page 440 pages. Available in PDF, EPUB and Kindle. Book excerpt: In addition to understanding chloroquine resistance, the recent emergence of a delayed clearance phenotype (DCP) and piperaquine resistance further warrant novel methods of probing molecular mechanisms of drug resistance. Mutations in the propeller domains of a Kelch domain-containing protein on chromosome 13 (K13) have been linked to DCP and traditional methods of quantifying cytostatic or cytocidal activities of drugs fail to distinguish K13-mutant parasites from wild-type parasites. In 2013, Witkowski et al. developed the ring-stage susceptibility assay (RSA) using dihydroartemisinin to correlate DCP with an in vitro measurement: increased parasite survival. This method was modified to investigate other endoperoxide drugs and of the seven compounds tested, OZ439 was only compound that circumvented the endoperoxide cross-resistance pattern.

Download or read book Studies on the Mechanism of Action and Mechanism of Resistance to Quinoline containing Antimalarial Drugs in Plasmodium Falciparum written by Mathirut Mungthin and published by . This book was released on 1998 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book A New Mechanism of Antimalarial Drug Resistance Regulated at the Epigenetic Level written by Sofía Mira Martínez and published by . This book was released on 2018 with total page 301 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria is responsible of almost half a million deaths every year. Currently, campaigns for the control and elimination of malaria are implemented in malaria endemic areas. However, drug resistance is one of the major impediments to achieve malaria elimination. In this thesis we have investigated how P. falciparum parasites develop resistance to some toxic compounds by functional variation linked to epigenetic regulation of clag3 genes. These genes present clonally variant expression and determine the formation of the main channel for the transport of solutes at the membrane of the infected RBC: Plasmodium Surface Anion Channel (PSAC). Hence, we hypothesized that P. falciparum parasites can modify the permeability of the membrane to specific solutes by epigenetic regulation of clag3 genes expression; this way, parasites could develop resistance to antimalarial drugs. To test this hypothesis, we have investigated the role of switches in clag3 expression in the acquisition of resistance to the antibiotic BS, the dynamics of clag3 genes expression in human infections and we have tested drugs susceptible to failure by this drug resistance mechanism. First, we show that BS pressure at low concentrations selected for parasites expressing clag3.1, whereas parasites exposed to higher concentrations of BS had repressed the expression of both clag3 genes. We did not find any mutation in the genome of these parasites that could explain the change in their phenotype. Thus, we concluded that parasites can develop resistance to toxic compounds through epigenetic regulation of clag3 genes. Then, we found that parasites collected from patients with uncomplicated malaria predominantly express one of the two paralogues, consistent with the property of mutually exclusive expression, previously described in lab-adapted parasite lines. Adaptation to culture conditions or selection with toxic compound results in isolate-dependent changes in clag3 expression, implying functional differences between the proteins encoded. We also observed that samples collected at day 9 post-infection in human experimental infections (when parasites had been in the peripheral blood for approximately one erythrocytic cycle) showed a mix of parasites expressing either clag3.1 or clag3.2, suggesting that the epigenetic memory of clag3 genes is reset during transmission stages. Finally, we tested whether other drugs, that are suspected to require facilitated transport to reach the cell, could be susceptible of failure by this drug resistance mechanism. We found that the antimalarial compounds T3 and T16 (bis-thiazolium salts) require the product of clag3 genes to enter the infected erythrocyte and that P. falciparum populations can develop resistance to these compounds by selection of parasites with dramatically reduced expression of both genes. The rest of the drugs that we tested might use alternative routes in which clag3 genes are not involved. We have described for the first time an antimalarial drug resistance mechanism regulated at the epigenetic level in P. falciparum parasites. This phenomenon may be of relevance for parasite adaptation to the presence of toxic compounds in human blood, selecting rapidly those parasites that present the less permeable phenotype and developing drug resistance in a single infection.

Download or read book Investigation of the Molecular Mechanism of Drug Resistance with Specific Reference to the Pfcrt Gene in Plasmodium Falciparum written by Yik-to Chung and published by . This book was released on 2011 with total page 226 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Handbook of Antimicrobial Resistance written by Matthias Gotte and published by Springer. This book was released on 2018-02-12 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: While many volumes have been written about various aspects of antimicrobial resistance, this book is a comprehensive reference work. All manifestations of resistance are addressed: viral; bacterial, parasitical and fungal are given dedicated sections. The underlining molecular mechanisms, which depend not only on the microbe but on the specific drug (target), are highly diverse. This work discusses and compares the biological, biochemical and structural aspects of resistance and its evolution.

Download or read book Bacterial Adaptation to Co resistance written by Santi M. Mandal and published by Springer Nature. This book was released on 2019-11-17 with total page 324 pages. Available in PDF, EPUB and Kindle. Book excerpt: The proposed book aims to understand the mechanism of survival of microorganisms in response to chemical stress in various ecological niches that suffer direct human intervention, more so the agricultural, domestic and hospital settings. Microbicides (e.g. disinfectants, antiseptics, fungicides, algaecides, insecticides and pesticides) are used rampantly to control undesirable microbes. Insecticides and pesticides are routinely used in agriculture which directly affect the microbial population in farms, orchards and fields. Health care environments are always stressed with disinfectants and antibiotics. It is always probable that microbicide-stressed microorganisms are in a dynamic state, displaced from one niche to the other. Some soil and water borne bacteria or their resistance determinants are also getting prominence in hospital settings after suffering selective pressure from agricides. In order to reveal the survival strategies of microbicidal-resistant microbes, it is of prime importance to know the mode of action of these complete range of microbicides (agricides to antibiotics). The present book intends to address these issues. There will be several chapters dealing with tolerance and cross resistance in microbes and bacteria in particular, dwelling in various niches. Till date, there is no consensus among scientists in theorizing molecular mechanisms to explain bacterial tolerance and their cross resistance to agricides and antibiotics.

Download or read book Antimalarial Natural Products written by A. Douglas Kinghorn and published by Springer Nature. This book was released on 2022-01-02 with total page 116 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume begins with a short history of malaria and follows with a summary of its biology. It then traces the fascinating history of the discovery of quinine for malaria treatment, and then describes quinine’s biosynthesis, its mechanism of action, and its clinical use, concluding with a discussion of synthetic antimalarial agents based on quinine’s structure. It also covers the discovery of artemisinin and its development as the source of the most effective current antimalarial drug, including summaries of its synthesis and biosynthesis, its mechanism of action, and its clinical use and resistance. A short discussion of other clinically used antimalarial natural products leads to a detailed treatment of additional natural products with significant antiplasmodial activity, classified by compound type. Although the search for new antimalarial natural products from Nature’s combinatorial library is challenging, it is very likely to yield new antimalarial drugs. This book thus ends by identifying ten natural products with development potential as clinical antimalarial agents.

Download or read book Biomedical Applications of Acridines written by Jan Ježek and published by Springer. This book was released on 2017-08-15 with total page 243 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book describes applications of acridines for the treatment of various neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and various prion diseases, and discusses the potential of acridines in neuro-regenerative medicine. Using modern data-mining software, it presents structures of acridines with nucleic acids and proteins and compares them with the native structures. Furthermore, the book presents modern methods of acridine synthesis, comparing them with the most useful conventional methods. Acridines interact with both nucleic acids and proteins, and due to their direct interactions with various enzymes, they can be suitable for the treatment of neurodegenerative diseases, inflammation, immunological disorders, and protozoal diseases. The characteristic spectral properties of acridines can be employed in labeling proteins, nucleic acids, lipids, and even cells and their compartments. Moreover, they can be applied in photodynamic therapy.

Download or read book Chemotherapy and Drug Resistance in Malaria written by Wallace Peters and published by . This book was released on 1987 with total page 822 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Microbial Products for Health Environment and Agriculture written by Pankaj Kumar Arora and published by Springer Nature. This book was released on 2021-09-21 with total page 381 pages. Available in PDF, EPUB and Kindle. Book excerpt: This edited volume discusses the role of various microbial products in healthcare, environment and agriculture. Several microbial products are directly involved in solving major health problems, agricultural and environmental issues. In healthcare sector, microbes are used as anti-tumor compounds, antibiotics, anti-parasitic agents, enzyme inhibitors and immunosuppressive agents. Microbial products are also used to degrade xenobiotic compounds and bio-surfactants, for biodegradation process. In agriculture, microbial products are used to enhance nutrient uptake, to promote plant growth, or to control plant diseases. The book presents several such applications of microbes in the ecosystems. The chapters are contributed from across the globe and contain up-to-date information. This book is of interest to teachers, researchers, microbiologists and ecologists. Also the book serves as additional reading material for undergraduate and graduate students of agriculture, forestry, ecology, soil science, and environmental sciences.

Download or read book Encyclopedia of Traditional Chinese Medicines Molecular Structures Pharmacological Activities Natural Sources and Applications written by Jiaju Zhou and published by Springer. This book was released on 2011-03-25 with total page 636 pages. Available in PDF, EPUB and Kindle. Book excerpt: This set of six volumes provides a systematic and standardized description of 23,033 chemical components isolated from 6,926 medicinal plants, collected from 5,535 books/articles published in Chinese and international journals. A chemical structure with stereo-chemistry bonds is provided for each chemical component, in addition to conventional information, such as Chinese and English names, physical and chemical properties. It includes a name list of medicinal plants from which the chemical component was isolated. Furthermore, abundant pharmacological data for nearly 8,000 chemical components are presented, including experimental method, experimental animal, cell type, quantitative data, as well as control compound data. The seven indexes allow for complete cross-indexing. Regardless whether one searches for the molecular formula of a compound, the pharmacological activity of a compound, or the English name of a plant, the information in the book can be retrieved in multiple ways.

Download or read book Medicinal and Aromatic Plants of the World Africa Volume 3 written by Mohamed Neffati and published by Springer. This book was released on 2017-09-07 with total page 415 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume in the series is devoted to Africa, a continent that possesses a vast treasure of medicinal plants and has produced some exclusive materials for the world market. This volume is expected to strengthen the medicinal plant sector in African countries by making comprehensive information on medicinal and aromatic plants available to policy-makers and entrepreneurs. It can be used to frame effective policies and create an environment conducive to the growth of the plant-based medicine industry, bringing economic benefit to African nations. It will help health organizations to improve the health of their people by using their own resources and a less expensive system of medicine, which is accepted by African society. It could also lead scientific communities to increase R&D activities in the field.

Download or read book Biodiversity and Chemotaxonomy written by Kishan Gopal Ramawat and published by Springer Nature. This book was released on 2019-11-10 with total page 318 pages. Available in PDF, EPUB and Kindle. Book excerpt: Plant classifications are based on morphological characters and it is difficult, particularly in small plants and grasses, to identify these below generic level on the basis of these characters using a dissecting microscope. Plant species have intra- and inter-specific variation in secondary metabolites which can be utilized as marker compounds for identification and classification of plants. Secondary metabolites are produced as a result of primary metabolism and the production of these compounds not only involves several genes but also it is an energy dependent process. Hence these products cannot be considered as insignificant for the plant and the environment. Modern tools of molecular biology and secondary metabolites present in them can definitively decide about classification of plants. Absence of correct identification of plant is associated to many problems of resource utilization. Due to wide availability of these tools, interest has revived in systematics and correct classification of plants based on these parameters for their sustainable utilization and resource management. The purpose of this book is to assess the potential of phytochemical and molecular tools in the systematic and classification of plants. The topics covered include species concept, barcoding and phylogenetic analysis, chemotaxonomy use of polyketides, carotenes, cuticular wax, volatile oils, biodiversity of corals, metazoans, Ruta and Echinocereus. It provides comprehensive and broad subject-based reviews, useful for students, teachers, researchers, and all others interested in the field. The field has been kept wide and general to accommodate the wide-ranging topics. This book will be useful to agriculturists, chemists, botanists, industrialists, and those involved in planning of crop plants.