Download or read book Analysis of Parasite Chloroquine Resistance Transporter Proteins and Their Roles in Drug Resistance Phenomena written by Bryce Riegel and published by . This book was released on 2020 with total page 444 pages. Available in PDF, EPUB and Kindle. Book excerpt: In this thesis, I measure drug transport efficiencies of multiple PvCRT isoforms heterologously expressed in yeast. I also measure drug transport for novel PPQR-associated PfCRT isoforms, and test whether an orthologue of PfCRT found in the closely related apicomplexan parasite Toxoplasma gondii (TgCRT), is a functional transporter of CQ, as part of a broader investigation of the role of TgCRT in the endolysosomal system of T. gondii.
Download or read book The Malaria Parasite s Chloroquine Resistance Transporter written by Robert Leon Summers and published by . This book was released on 2017 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The malaria parasite's chloroquine resistance transporter: An exploration of its interactions with drugs and of its evolution as a drug transporter Abstract: Initially identified as the primary determinant of chloroquine resistance in the malaria parasite Plasmodium falciparum, mutations in the 'chloroquine resistance transporter' (PfCRT) can influence the parasite's susceptibility to diverse molecules. The ability of PfCRT to affect the activity of so many compounds is likely to be a product of its location at the membrane of the parasite's digestive vacuole - an acidic compartment in which many types of drugs accumulate, act, and/or are activated. The Xenopus laevis oocyte system enables the functional expression of PfCRT and has been used to demonstrate that a mutant isoform of PfCRT mediates the efflux of chloroquine from the vacuole (i.e., away from its site of action), whereas the wild-type protein lacks this activity. However, the evolution of chloroquine transport activity by PfCRT has yet to be explored, and little is known of how PfCRT interacts with diverse compounds. The overarching aim of this study was to understand how mutations in PfCRT confer chloroquine transport activity and alter the parasite's susceptibility to diverse pharmacons. A kinetic analysis of the inhibition of PfCRT-mediated chloroquine transport by verapamil, a compound which partially restores the activity of chloroquine against drug-resistant parasites, was undertaken in the oocyte system. The findings of this work revealed verapamil to be a partial-mixed-type inhibitor of the transporter, and suggested that the mutations required for chloroquine transport introduce multiple substrate-binding sites into PfCRT. A series of complementary assays were then applied to examine the interactions of PfCRT with a range of compounds to identify, and distinguish between, PfCRT substrates and inhibitors. Using the oocyte system, two new classes of compounds were identified as potent inhibitors of the PfCRT-mediated transport of chloroquine. Transgenic parasite lines that are isogenic except for their pfcrt allele were employed, in conjunction with an assay that indirectly detects the transport of drugs out of the parasite's digestive vacuole, to further characterise these compounds. The resulting data revealed that most of these molecules are not substrates of the mutant transporter. Furthermore, parasite proliferation assays demonstrated that the compounds possessed enhanced activities against parasites harbouring mutant PfCRT. Structure-activity relationships were consistent with these compounds binding to multiple points of attachment within PfCRT via lipophilic and electrostatic interactions. Measurements of chloroquine transport via diverse isoforms of PfCRT (as well as by a series of chimeric proteins) were also undertaken in the oocyte system. These analyses revealed that multiple mutational pathways lead to saturable chloroquine transport via PfCRT. The finding that diverse PfCRT variants are all limited in their capacity to transport chloroquine suggests that resistance could be overcome by re-optimising the chloroquine dosage. Moreover, the results of this study indicated that the remodelling of PfCRT for chloroquine transport required a complex reorganisation of interacting residues. These studies support the idea that, in addition to being a mediator of multidrug resistance, PfCRT is itself a viable drug target. Antimalarial therapies could be formulated to exert opposing selection forces upon PfCRT, thereby exploiting a key resistance mechanism and prolonging drug efficacy against this important human pathogen.
Download or read book Functional Studies on the Chloroquine Resistance Transporter PfCRT and the HECT E3 Ubiquitin protein Ligase PfUT in Plasmodium Falciparum written by Monika Jankowska-Döllken and published by . This book was released on 2019* with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Posttranslational modifications (PTMs) affect fundamental cellular functions of the human malaria parasite Plasmodium falciparum, including regulation of protein stability, metabolism, proliferation, apoptosis and signal transduction. This study investigates the importance of phosphorylation and ubiquitination in modulating the parasite intraerythrocytic development, as well as their implication in antimalarial drug resistance. The chloroquine resistance transporter PfCRT is a drug-metabolite carrier annotated as a prominent determinant of parasite's reduced susceptibility to quinoline drugs. PfCRT is posttranslationally modified by phosphorylation and palmitoylation. However, the role of these PTMs in regulation of PfCRT function is not fully resolved. Chemical and genetic approaches employed in the current study revealed the relevance of PfCRT phosphorylation at serine 33 in regulating the drug resistance-mediating function of this transporter and in vitro fitness of the parasite. The PfCRT allelic exchange mutants, in which serine 33 was replaced by alanine showed increased sensitivity to chloroquine and quinine. Moreover, PfCRT serine 33 substitution by phospho-mimicking amino acids, glutamic and aspartic acid, could respectively partially and fully, restore the resistance phenotype. The fitness variation between the PfCRT mutants was linked to differences in merozoite numbers and their invasion efficiencies, with alanine mutants displaying a significant advantage in this regard. Identification of a kinase implicated in this phenomenon is desired, as its inhibition in combination with chloroquine could reduce or prevent the further spread of resistance. A HECT E3 ubiquitin ligase, termed ubiquitin transferase PfUT, is a novel candidate gene for multifactorial resistance to quinine. PfUT was shown to localize to the parasite's ER/Golgi complex, but its role in reduced susceptibility to quinine and its physiological function remain unclear. Characterization of PfUT was attempted by a glmS ribozyme-based conditional knockdown of encoding it gene, generated using the CRISPR-Cas9 genome editing technology. Unexpectedly, integration of the glmS sequence resulted in a 2-fold increase in PfUT transcripts correlated with protein levels. PfUT overexpression, in turn, led to S phase-associated lengthening of parasite's cycle, reflected in impaired growth. Glucosamine-induced incomplete downregulation partially restored the wild type phenotype. Moreover, the transgenic parasites exhibited an enhanced susceptibility to quinine and quinidine. An alternative disruption of the pfut locus via a selection-linked integration (SLI-TGD) strategy was unsuccessful, despite multiple attempts. These results underline the importance of PfUT in parasite proliferation and survival. However, a direct proof of PfUT's association with quinine resistance and identification of its biological substrates await further investigation.
Download or read book Studies of Malarial Parasite Chloroquine Resistance Transporter and Kinase Proteins Key Targets for Evolving Drug Therapies written by Matthew Ryan Hassett and published by . This book was released on 2017 with total page 512 pages. Available in PDF, EPUB and Kindle. Book excerpt: I have continued the use of an optimized CRT expression system in S. cerevisiae to elucidate drug transport ability. CQ resistance (CQR) is well understood in P. falciparum, but in Plasmodium vivax (another species of malaria), CQR remains a mystery. Multiple mutations in PfCRT are characteristic of drug resistant isolates, and contrary to PfCRT, the P. vivax orthologue (named PvCRT) primarily shows only single mutations in CRT. In this thesis, I measure the drug transport efficiencies of multiple Pf and PvCRT isoforms. My results show that there is a range of quinolone drug transport across the isoforms analyzed. Additionally, some CQR isolates expressing certain CRT isoforms likely have other genetic events that shape CQR.
Download or read book Identifying the Minimal Number of Mutations Required for Chloroquine Transport Via the Malaria Parasite s Chloroquine Resistance Transporter written by Tegan Dolstra and published by . This book was released on 2014 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: As resistance to the current frontline antimalarial drug, artemisinin, begins to spread through the malaria parasite population, efficacious alternatives are desperately required. One potential, relatively cheap source of new drugs is previously efficacious antimalarials that have fallen out of use due to widespread resistance. Of these, chloroquine (CQ) is particularly promising. CQ kills malaria parasites by interfering with the neutralisation of toxic haem waste products generated during haemoglobin digestion in the parasite's digestive vacuole (DV). A gold-standard antimalarial in the mid-20th century, the use of CQ is now severely limited due to the emergence and subsequent spread of CQ resistant (CQR) parasites. CQR parasites accumulate far less CQ in their DV than do CQ sensitive parasites. The main determinant of CQ resistance is mutations in a transport protein, the Plasmodium falciparum Chloroquine Resistance Transporter (PfCRT), which is located in the DV membrane. Martin et al. (2009) have shown using a heterologous Xenopus oocyte system that a CQR haplotype of PfCRT is capable of CQ transport, whereas the wild-type protein is not. Thus, it is proposed that CQ resistance is mediated by mutant PfCRT transporting CQ out of the DV and away from the drug's site of action. Here, I present a detailed analysis of the roles of the eight PfCRT mutations found in the CQR strain 'Dd2'. I expressed 29 PfCRT variants harbouring different combinations of these mutations in Xenopus oocytes. I then measured the ability of each variant to transport CQ to determine the minimal mutational requirements for CQ transport via PfCRT. I found that the combination of two mutations - K76T and N75E - was sufficient to induce low-level CQ transport, while a combination of four mutations - K76T, N75E, A220S and Q271E - allowed the protein to transport CQ at levels comparable to the Dd2 version of PfCRT. These findings provide novel and unexpected insights into the workings of a protein that is a key determinant of drug resistance in the malaria parasite.
Download or read book Malaria written by Institute of Medicine and published by National Academies Press. This book was released on 1991-02-01 with total page 312 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria is making a dramatic comeback in the world. The disease is the foremost health challenge in Africa south of the Sahara, and people traveling to malarious areas are at increased risk of malaria-related sickness and death. This book examines the prospects for bringing malaria under control, with specific recommendations for U.S. policy, directions for research and program funding, and appropriate roles for federal and international agencies and the medical and public health communities. The volume reports on the current status of malaria research, prevention, and control efforts worldwide. The authors present study results and commentary on the: Nature, clinical manifestations, diagnosis, and epidemiology of malaria. Biology of the malaria parasite and its vector. Prospects for developing malaria vaccines and improved treatments. Economic, social, and behavioral factors in malaria control.
Download or read book Saving Lives Buying Time written by Institute of Medicine and published by National Academies Press. This book was released on 2004-09-09 with total page 384 pages. Available in PDF, EPUB and Kindle. Book excerpt: For more than 50 years, low-cost antimalarial drugs silently saved millions of lives and cured billions of debilitating infections. Today, however, these drugs no longer work against the deadliest form of malaria that exists throughout the world. Malaria deaths in sub-Saharan Africaâ€"currently just over one million per yearâ€"are rising because of increased resistance to the old, inexpensive drugs. Although effective new drugs called "artemisinins" are available, they are unaffordable for the majority of the affected population, even at a cost of one dollar per course. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance examines the history of malaria treatments, provides an overview of the current drug crisis, and offers recommendations on maximizing access to and effectiveness of antimalarial drugs. The book finds that most people in endemic countries will not have access to currently effective combination treatments, which should include an artemisinin, without financing from the global community. Without funding for effective treatment, malaria mortality could double over the next 10 to 20 years and transmission will intensify.
Download or read book Assessment of Long Term Health Effects of Antimalarial Drugs When Used for Prophylaxis written by National Academies of Sciences, Engineering, and Medicine and published by National Academies Press. This book was released on 2020-04-24 with total page 427 pages. Available in PDF, EPUB and Kindle. Book excerpt: Among the many who serve in the United States Armed Forces and who are deployed to distant locations around the world, myriad health threats are encountered. In addition to those associated with the disruption of their home life and potential for combat, they may face distinctive disease threats that are specific to the locations to which they are deployed. U.S. forces have been deployed many times over the years to areas in which malaria is endemic, including in parts of Afghanistan and Iraq. Department of Defense (DoD) policy requires that antimalarial drugs be issued and regimens adhered to for deployments to malaria-endemic areas. Policies directing which should be used as first and as second-line agents have evolved over time based on new data regarding adverse events or precautions for specific underlying health conditions, areas of deployment, and other operational factors At the request of the Veterans Administration, Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis assesses the scientific evidence regarding the potential for long-term health effects resulting from the use of antimalarial drugs that were approved by FDA or used by U.S. service members for malaria prophylaxis, with a focus on mefloquine, tafenoquine, and other antimalarial drugs that have been used by DoD in the past 25 years. This report offers conclusions based on available evidence regarding associations of persistent or latent adverse events.
Download or read book Treatment and Prevention of Malaria written by Henry M. Staines and published by Springer Science & Business Media. This book was released on 2012-01-06 with total page 318 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria has defeated previous efforts at eradication and remains a massive global public health problem despite being readily preventable and treatable. It is a devastating disease that also extracts huge economic costs from the poorest countries in endemic regions. Starting with an overview of the disease and its current political, financial and technical context, this Milestones in Drug Therapy volume describes the history, chemistry, mechanisms of action and resistance, preclinical and clinical use, pharmacokinetics and safety and tolerability of the current range of antimalarial drugs. There is particular emphasis on artemisinins and related peroxides, as these drugs have now become the frontline treatment for malaria. Next generation antimalarials, molecular markers for detecting resistance, the importance of diagnostics and disease prevention are also covered in detail.
Download or read book Malaria Drugs Disease and Post genomic Biology written by David Sullivan and published by Springer Science & Business Media. This book was released on 2006-01-09 with total page 447 pages. Available in PDF, EPUB and Kindle. Book excerpt: Despite rapid increases in knowledge, malaria continues to kill more than a million people each year and causes symptomatic disease in a further 300 million individuals. This volume brings some of the world's best investigators to describe recent advances in both the scientific and clinical aspects of malaria, and bridges between the two.
Download or read book Mechanisms of antibiotic resistance written by Jun Lin and published by Frontiers Media SA. This book was released on 2015-06-01 with total page 226 pages. Available in PDF, EPUB and Kindle. Book excerpt: Antibiotics represent one of the most successful forms of therapy in medicine. But the efficiency of antibiotics is compromised by the growing number of antibiotic-resistant pathogens. Antibiotic resistance, which is implicated in elevated morbidity and mortality rates as well as in the increased treatment costs, is considered to be one of the major global public health threats (www.who.int/drugresistance/en/) and the magnitude of the problem recently prompted a number of international and national bodies to take actions to protect the public (http://ec.europa.eu/dgs/health_consumer/docs/road-map-amr_en.pdf: http://www.who.int/drugresistance/amr_global_action_plan/en/; http://www.whitehouse.gov/sites/default/files/docs/carb_national_strategy.pdf). Understanding the mechanisms by which bacteria successfully defend themselves against the antibiotic assault represent the main theme of this eBook published as a Research Topic in Frontiers in Microbiology, section of Antimicrobials, Resistance, and Chemotherapy. The articles in the eBook update the reader on various aspects and mechanisms of antibiotic resistance. A better understanding of these mechanisms should facilitate the development of means to potentiate the efficacy and increase the lifespan of antibiotics while minimizing the emergence of antibiotic resistance among pathogens.
Download or read book Antimicrobial Resistance written by World Health Organization and published by . This book was released on 2014 with total page 232 pages. Available in PDF, EPUB and Kindle. Book excerpt: Summary report published as technical document with reference number: WHO/HSE/PED/AIP/2014.2.
Download or read book Guidelines for the Treatment of Malaria Third Edition written by World Health Organization and published by World Health Organization. This book was released on 2015-08-13 with total page 317 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria remains an important cause of illness and death in children and adults in countries in which it is endemic. Malaria control requires an integrated approach including prevention (primarily vector control) and prompt treatment with effective antimalarial agents. Malaria case management consisting of prompt diagnosis and effective treatment remains a vital component of malaria control and elimination strategies. Since the publication of the first edition of the Guidelines for the treatment of malaria in 2006 and the second edition in 2010 all countries in which P. falciparum malaria is endemic have progressively updated their treatment policy from use of ineffective monotherapy to the currently recommended artemisinin-based combination therapies (ACT). This has contributed substantially to current reductions in global morbidity and mortality from malaria. Unfortunately resistance to artemisinins has arisen recently in P. falciparum in South-East Asia which threatens these gains. This third edition of the WHO Guidelines for the treatment of malaria contains updated recommendations based on a firmer evidence base for most antimalarial drugs and in addition include recommendation on the use of drugs to prevent malaria in groups at high risk. The Guidelines provide a framework for designing specific detailed national treatment protocols taking into account local patterns of resistance to antimalarial drugs and health service capacity. It provides recommendations on treatment of uncomplicated and severe malaria in all age groups all endemic areas in special populations and several complex situations. In addition on the use of antimalarial drugs as preventive therapy in healthy people living in malaria-endemic areas who are high risk in order to reduce morbidity and mortality from malaria. The Guidelines are designed primarily for policy-makers in ministries of health who formulate country-specific treatment guidelines. Other groups that may find them useful include health professionals and public health and policy specialists that are partners in health or malaria control and the pharmaceutical industry. The treatment recommendations in the main document are brief; for those who wish to study the evidence base in more detail a series of annexes is provided with references to the appropriate sections of the main document.
Download or read book Antimicrobial Resistance in Developing Countries written by Aníbal de J. Sosa and published by Springer Science & Business Media. This book was released on 2009-10-08 with total page 553 pages. Available in PDF, EPUB and Kindle. Book excerpt: Avoiding infection has always been expensive. Some human populations escaped tropical infections by migrating into cold climates but then had to procure fuel, warm clothing, durable housing, and crops from a short growing season. Waterborne infections were averted by owning your own well or supporting a community reservoir. Everyone got vaccines in rich countries, while people in others got them later if at all. Antimicrobial agents seemed at first to be an exception. They did not need to be delivered through a cold chain and to everyone, as vaccines did. They had to be given only to infected patients and often then as relatively cheap injectables or pills off a shelf for only a few days to get astonishing cures. Antimicrobials not only were better than most other innovations but also reached more of the world’s people sooner. The problem appeared later. After each new antimicrobial became widely used, genes expressing resistance to it began to emerge and spread through bacterial populations. Patients infected with bacteria expressing such resistance genes then failed treatment and remained infected or died. Growing resistance to antimicrobial agents began to take away more and more of the cures that the agents had brought.
Download or read book Drug Resistance in Bacteria Fungi Malaria and Cancer written by Gunjan Arora and published by Springer. This book was released on 2017-03-21 with total page 629 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book is a compilation of past and recent knowledge in the field of emerging drug resistance. The book covers major aspects of drug resistance in bacteria, fungi, malaria, and cancer.Human survival on earth is constantly threatened by disease and syndrome. From the early days, the aim of research in medicine was to find therapeutic agents that can improve the quality of human life. Although humans are dependent on natural compounds from early days their dependence of drugs increased excessively in last century. The advances in chemistry and biology have helped researchers to identify the drugs that have improved treatment of many diseases. The primary factor for treatment of these diseases is dependent on the efficacy of drugs available. The development of resistance to these drugs is one of the major hindrances. Although there are number of books available on this topic, “drug resistance” biology across kingdoms has never been discussed in a coherent way.
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 Combination Therapy Against Multidrug Resistance written by Mohmmad Younus Wani and published by Academic Press. This book was released on 2020-04-30 with total page 270 pages. Available in PDF, EPUB and Kindle. Book excerpt: Combination Therapy against Multidrug Resistance explores the potential of combination therapy as an efficient strategy to combat multi-drug resistance. Multidrug resistance (MDR) occurs when microorganisms such as bacteria, fungi, viruses, and parasites are excessively exposed to antimicrobial drugs such as antibiotics, antifungals, or antivirals, and in response the microorganism undergoes mutations or develops different resistance mechanisms to combat the drug for its survival. MDR is becoming an increasingly serious problem in both developed and developing nations. Bacterial resistance to antibiotics has developed faster than the production of new antibiotics, making bacterial infections increasingly difficult to treat, and the same is true for a variety of other diseases. Combination therapy proves to be a promising strategy as it offers potential benefits such as a broad spectrum of efficacy, greater potency than the drugs used in monotherapy, improved safety and tolerability, and reduction in the number of resistant organisms. This book considers how combination therapy can be applied in multiple situations, including cancer, HIV, tuberculosis, fungal infections, and more. Combination Therapy Against Multidrug Resistance gathers the most relevant information on the prospects of combination therapy as a strategy to combat multridrug resistance and helping to motivate the industrial sector and government agencies to invest more in research and development of this strategy as a weapon to tackle the multidrug resistance problem. It will be useful to academics and researchers involved in the development of new antimicrobial or antiinfective agents and treatment strtategies to combat multidrug resistance. Clinicians and medical nurses working in the field of infection prevention and control (IPC) will also find the book relevant Explores strategic methods with investigation of both short- and long-term goals to combat multidrug resistance Presents a broad scope to understand fully the ways to apply combined therapy to multidrug resistance Provides an overview of combination therapy, but also includes specific cases such as cancer, tuberculosis, HIV and malaria
