Course Information Document 2023-2024
Welcome to the final year of your programme. One of the aims of the final year is to prepare you for the years ahead. The teaching will be structured differently, and you will be encouraged to work independently. We expect you to develop a breadth to your thinking and writing. This is the time to bring together knowledge gained during the past three years, looking for general principles which can be used productively. This mature approach should be expressed in your coursework, project report and examination answers. The key to success in final year is good time-management.
We recommend that you read this Course Information Document at the start of your final year.
In addition, there is important information about regulations, assessment and progression in the Life Sciences Handbook: Regulations & Advice; again, you should read this document at the start of the year and you must refer to it as necessary.
Please keep this Course Information Document for future reference after you graduate; you may need to provide course details for further study or other training.
While the information contained in the document is correct at the time of printing, it may be necessary to make changes. Check your online timetable, Moodle and your email messages regularly.
Course Coordinator: Prof Michael Barrett
Email: Michael.Barrett@glasgow.ac.uk
Deputy Course Coordinator: Dr Lisa Ranford-Cartwright
Email: Lisa.Ranford-Cartwright@glasgow.ac.uk
Programme Coordinator: Dr Nicola Veitch
Email: Nicola.Veitch@glasgow.ac.uk
Teaching staff names can be found on your online timetable and contact details can be found on the University website Staff A-Z
Prof Paul Langford, Imperial College London
The Life Sciences Office is located in Room 353 of the Sir James Black Building. Opening hours for enquiries are: Monday to Friday: 9:30am to 4:30pm.
Course Code
BIOL4030
Course Title
Chemotherapy, Resistance and Parasite Control 4B option
Academic Session
2023-24
Short Description of the Course
This option explores current practice, research and ideas in anti-parasite chemotherapy, resistance and parasite control. This includes drug discovery, drug treatment, vaccination and vector control. Problems in drug resistance are also studied. The course will enhance student ability in acquisition, interpretation and discussion of experimental data.
Requirements of Entry
Normally, only available to final-year School of Life Sciences students in a Degree Group B (Biomolecular Sciences group) or Degree Group D (Infection & Immunity group) programme. Visiting students may be allowed to enrol, at the discretion of the School of Life Sciences Chief Adviser and the Course Coordinator.
Associated Programmes
This course is offered by the Microbiology programme.
Available to visiting students
Yes
Available to Erasmus students
Yes
Typically offered
Semester 2
Timetable
This option is assigned to block S2-B. There are normally 3 hours of teaching on Tuesdays, which may be split over more than one session. However, sessions may be scheduled for 2 hours and 4 hours in alternate weeks instead.
Course Aims
The main aim of this course is to provide an overview on how parasitic infections are, and could be, controlled, with an emphasis on chemotherapy but also covering vaccines and vector control.
Intended Learning Outcomes of Course
By the end of this course, students will be able to:
· evaluate methods used in controlling parasitic infections;
· evaluate methodologies used in developing novel approaches to drug development (including understanding resistance problems), vaccination and vector control;
· evaluate the fundamental biochemical basis of drug action.
Minimum Requirements for Award of Credits
Students must submit at least 75% by weight of the components (including examinations) of the course’s summative assessment.
Description of Summative Assessment
The course will be assessed by a 2-hour examination (75%) and in-course assessment consisting of an essay (25%).
Are reassessment opportunities normally available for all summative assessments in this course
Not applicable for Honours courses
Formative Assessment and Feedback
A formative assessment session will provide training in writing final Honours examination-style essays. Students will discuss past exam questions and what level of content is expected at each grade.
Staff will provide verbal feedback during student-led teaching sessions. Individual verbal feedback will be given by staff for a flash presentation; other students may also provide useful feedback comments. Generic feedback on the general performance of the class will be provided for the essay, along with individual written feedback.
Examination Diet
April/May
Total Exam Duration
120 minutes
Drugs work by interfering with normal cellular function, leading ultimately to cell death. In order to work, drugs need to interact with particular targets. Selective toxicity can come about when a chemical interferes with an enzyme or receptor found in one cell type but not another. An enzyme whose function is more important in one cell type than another can also be selectively targeted. Cells are replete with proteins, any of which could, in principle, be a drug target. In the quest for new drugs, it is useful to know which proteins within a cell may be targeted. It is therefore necessary to validate proteins that are drug targets. A number of different methods can be employed to allow us to validate drug targets. For example, in many parasites it is now possible to delete genes from the parasite’s genome and the technology adapted from CRISPR/Cas9 is greatly enhancing this. In order to be considered a drug target the gene should normally be essential. RNA interference, and the use of inducibly expressed genes, can contribute to this validation process. It is also possible to validate a drug target by chemical means. Chemical validation involves using a compound that selectively inhibits an enzyme or receptor and which also kills a cell. In this latter case, however, it is also necessary to show that the death phenotype associated with that particular inhibitor is specific and not due to the compound also interfering with another target within the cell. Also of importance is a knowledge of whether a given protein is amenable to inhibition by chemicals that have properties that make them useful as drugs (i.e. chemicals that can safely be given to humans and distribute within the body to find and enter parasites). Chemoinformatics approaches, looking at protein structure and predicting how drugs bind to them, are increasingly important in this regard.
To learn about how drug targets can be identified in parasites using chemical and genetic means
At the end of the session you should be able to:
understand how drug targets can be identified through genetic means;
understand how drug targets can be identified through chemical means;
understand how an understanding of protein structure and ligand binding can influence target selection;
give examples of validated drug targets from parasitic trypanosomatids and apicomplexan parasites.
A list of recommended reading is provided on Moodle
Frearson JA, et al. N-myristoyltransferase inhibitors as new leads to treat sleeping sickness. Nature. 2010;464:728-32
What is myristate and why is it linked to some proteins?
Describe the assay for N-myristoyl transferase
Why did lack of activity of DDD85635 indicate a role for nitrogen?
Why is it important that DDD85646 is orally available?
What is the difference between trypanocidal and trypanostatic drugs?
What evidence is shown that DDD85646 inhibits NMT in trypanosomes?
Why was the Leishmania NMT used in drug binding studies?
How can X-ray crystallography influence drug design?
Why might DDD85646 fail to clear trypanosomes in the brain?
What risks are there for host-toxicity with DDD85646?
Drugs are low molecular weight chemicals that interfere with specific metabolic processes leading to cell death. In order to act as a drug a chemical must interact with a particular drug target and inhibit the target. Rational drug design involves identifying a drug target and then using computer based, or other, modelling in order to design compounds that will make specific interactions with that target. In addition to the rational approach, with many compounds having been synthesised for a multitude of reasons over many years, it is also possible to Test libraries of compounds against drug targets that have been isolated and for which assays of activity exist. Frequently it has proven effective to Test directly for activity against parasites themselves and both chemical and natural product libraries are used in this regard. There is, however, more to drug development than simple design of inhibitors of enzymes or receptor targets. It is also necessary that chemicals have properties within hosts that enable them to reach and penetrate parasites, whilst at the same time not inducing adverse events through interactions with the host. These properties that relate to the pharmacokinetics and pharmacodynamics of a drug are as important, if not more important, to the development process as the drug’s ability to inhibit particular targets.
To learn how chemicals can be designed to act as drugs
At the end of the session you should be able to:
understand how chemicals can interact with cellular drug targets;
understand how such chemicals can be identified;
understand how distribution of chemicals within the body affects the ability to affect parasites and drug targets.
A list of recommended reading is provided on Moodle
Wyllie S, et al. (2018) Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis. Nature. 560, 192- 197.
How were the diaminothiazole series discovered?
Why was increased polarity desired in compound 5 (Fig 1) ?
Why did the authors Test for Cytochrome P450 inhibition (p194, line 6)?
How was CRK12 initially identified as a potential target of the pyrazolopyrimidines?
How was this confirmed?
Why was a homology model against human CDK9 built?
Where are the inhibitors proposed to bind?
What experiments could be performed to prove the binding?
What advantages cold these compounds have as anti-leishmaniasis drugs beyond current drugs?
What barriers to further development need to be overcome?
The lecture will introduce primary pathways of pyrimidine, purine and folate metabolism in protozoa. Their roles in protozoan physiology will be discussed. Specific examples of purines, pyrimidines and folates with chemotherapeutic potential will be identified and their mode of action highlighted.
The subsequent presentation and discussion will focus on the specific questions raised in the paper and applying the lecture material to purine-based drugs. It is essential that everybody has read the paper and is able to contribute to the discussion.
To introduce purine, pyrimidine and folate metabolism in protozoa and identify possible therapeutic strategies arising from these biochemical pathways
At the end of the session you should be able to:
discuss the relative importance of the various pathways and their role in protozoan physiology;
understand why purine and folate metabolism are considered good drug targets in most protozoa, but pyrimidine metabolism is not;
give specific examples of therapeutic interventions based on these pathways.
A list of recommended reading is provided on Moodle
Vodnala SK, Lundbäck T, Yeheskieli E, Sjöberg B, Gustavsson AL, Svensson R, Olivera G, Eze AA, De Koning HP, Hammarström LGJ, and Rottenberg ME (2013) Investigation of the trypanocidal SAR of synthetic cordycepin analogues. J Med Chem 56:9861-9873
Previous work with cordycepin leading up to this study
Why does cordycepin display a very different activity against trypanosomes in vivo and in vitro?
What is a ‘structure-activity-relationship’ study (SAR)?
What were the aims of doing a SAR study for cordycepin?
In what way does this paper illustrate that antiprotozoal drugs need to be optimised both for human and parasite metabolism?
Why should any cordycepin analogue elected for further drug development be a substrate of T. brucei adenosine kinase?
What is said about the preclinical properties of 2-fluorocordycepin and why is it important?
Why was transport of cordycepin and its analogues investigated, and what was found?
What is being reported about the synthesis of 2-halogenated cordycepins and why is it important?
Transport proteins or transporters are required by all living cells to facilitate the passage of hydrophilic molecules, such as metabolic intermediates and nutrients, across biomembranes. Protozoa express a multitude of highly efficient transporters for uptake of nutrients from their environment, as well as numerous transporters that are located in the membranes of intracellular organelles such as mitochondria and glycosomes. In many, but not all, cases the parasites are totally dependent on the transporters for their source of essential nutrients. Examples include glucose and purine nucleosides. In this lecture we will look at the characteristics of protozoan transporters and how they differ from their counterparts in human cells. We will discuss whether these characteristics make them good drug targets in themselves or whether their therapeutic potential rather lies in mediating the efficient internalisation of specifically targeted antiprotozoal drugs.
To identify the unique characteristics of protozoan transporters, and discuss their potential role in chemotherapy of parasitic disease
At the end of the session you should be able to:
Compare parasite transporters and host transporters;
Understand the implications for efficiency of nutrient acquisition by protozoa;
Understand the difficulties in targeting transporters localised in the plasma membrane with inhibitors as a chemotherapeutic strategy;
Identify the possibilities of using transporters for the selective targeting of therapeutic agents to pathogens.
A list of recommended reading is provided on Moodle
Graf FE, Ludin P, Wenzler T, Kaiser M, Pyana P, Büscher P, De Koning HP, Horn D, and Mäser P (2013) Aquaporin 2 mutations in Trypanosoma b. gambiense field isolates correlate with decreased susceptibility to pentamidine and melarsoprol. PLoS Negl Trop Dis 7:e2475
What are the current used for the various stages and forms of sleeping sickness?
Is resistance to these drugs at clinically important levels?
What are the current models for the resistance mechanisms and how is the current paper investigating whether these models apply to the clinical setting?
Discuss whether it is better in such a study to have strains from various African regions, quite far apart, or to have many isolates for a single sleeping sickness focus.
What changes were found in the AQP2-AQP3 locus, and did all changes correlate with drug resistance?
To what extent did the TbAT1 gene contribute to drug resistance?
In order to identify new targets suitable for the treatment of parasites it is necessary to understand and dissect the precise functions of the potential targets. One of the pre-requisites for a pathway or protein to be a suitable target for chemotherapy is that it is essential for the survival of the parasite. Another one is that the protein either is absent from mammals or sufficiently different in structure or function from its mammalian counterpart to make specific inhibition of the molecule or pathway feasible. Parasite peptidases fulfil a number of these requirements. Firstly they play pivotal roles for/in several key pathways in protozoan parasites aiding them to invade, survive, develop in and egress from their hosts. Parasite peptidases differ in many ways from those found in humans particularly through the roles they play in the parasites. This session will describe their essential roles and the possible ways by which these proteins can be exploited for the design of new antiparasitic therapies.
To understand the key functions that peptidases have for protozoan parasites throughout their different life cycle stages and for their interactions with the host
To understand the different roles that peptidases have for the development and survival of parasitic protozoa.
To understand which of these key enzymes are suitable drug targets or vaccine candidates.
A list of recommended reading is provided on Moodle
Khare, S., et al. (2016) Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness.Nature. 537, 229-233.
Why were the authors interested in co-targeting T. brucei, T.cruzi and Leishmania?
Why did they also screen mammalian cells?
How did they move from an azabendazole to a triazolopyrimidine type strcture
How was oral bioavailability determined for GNF6702 and why was this important
Why was activity in stage 2 models of African trypanosomiasis particularly important
Why did the authors focus on T. cruzi to seek a mode of action?
What route did the take to find that?
What was the predicted target and how was this proven to be the actual target?
Why does the inhibitor bind to trypanosomatid proteasomes but not human proteasomes?
Why was modelling used to predict the binding of inhibitor to target?
What experiments could be done to prove this?
What hurdles need to be crossed in order to convert this lead compound into a useful drug?
The lecture will give some basic background on how reactive oxygen species are formed and why they are dangerous and need to be removed. It will introduce the major antioxidant systems present in aerobic organisms focussing on protozoan parasites in comparison with their host organisms.
The major antioxidant systems of protozoan parasites focussing on trypanosomatids and Plasmodium will be described and compared to those of their mammalian hosts. The suitability of these systems for the design of new antiparasitic drugs will be discussed.
To understand how oxidative stress is generated
To understand which mechanisms protect the parasites from oxidative stress
To identify whether parasite-specific antioxidants and their metabolism are suitable drug targets
At the end of the session you should be able to:
describe how reactive oxygen species are generated and why they are harmful;
describe the role of enzymes and metabolites that eukaryotes use to manage oxidative stress;
understand that interfering with the thiol redox balance can result in parasite death;
discuss drugs that can diminish a parasite’s capacity to deal with stress.
A list of recommended reading is provided on Moodle
Kehr S, Sturm N, Rahlfs S, Przyborski JM, Becker K. (2010) Compartmentation of redox metabolism in malaria parasites. PLoS Pathog. 6(12):e1001242.
Which antioxidant systems are present in the malaria parasites?
What methods were used to show the localisation of the antioxidant proteins?
What is the mechanism that allows dual targeting of antioxidant proteins in Plasmodium falciparum and how was this hypothesis Tested?
What are the implications of multiple/dual targeting of redox active proteins in Plasmodium?
Lipids are key components of cellular membranes. They also play important roles in cell signalling and have other roles within cells too. The amphipathic nature of membrane lipids is key to their function. As lipids are essential to cells, they can be targeted by drugs. Moreover, enzymatic pathways involved in their biosynthesis can also be drug targets. The biosynthesis of membrane phospholipids in Plasmodium parasites offers an excellent example. Fatty acid biosynthetic pathways in both trypanosomatids and apicomplexan pathways have been successfully targeted by drugs although in both cases unexpected “off-target” effects of drugs have led to the discovery of novel features of fatty acid biosynthesis in these parasites.
To learn about lipid structure and function, and how lipids and the enzymes involved in their biosynthesis can be targeted by drugs
At the end of the session you should be able to:
understand structure, function and synthesis of lipids;
understand how lipids can be targeted by chemical agents;
give examples of drugs in clinical use, and also at the experimental stage that act on lipid metabolism in protozoa.
A list of recommended reading is provided on Moodle
Brancucci NMB, et al (2017) Lysophosphatidylcholine regulates sexual stage differentiation in the human malaria parasite Plasmodium falciparum. Cell. 171, 1532-1544.
Why is targeting gametocytes an attractive malaria intervention?
Why would an abundance of LysoPC be an inhibitory factor for sexual commitment? What does an increase in sexual commitment suggest for the parasite?
What are the steps involved in sexual commitment at the chromatin and transcription factor level?
How did they determine commitment rate of parasites between different media conditions?
Why did LysoPC analogs not affect sexual commitment?
Why is the LysoPC and the Kennedy Pathway so important for P. falciparum?
What role does PMT have in parasite survival?
Given the interplay between lipid metabolism and sexual commitment how might you manipulate this to tackle malaria infections?
Polyamines are essential for growth and differentiation and it was shown that fast growing cells such as cancer cells have an increased requirement for these metabolites. Therefore polyamine metabolism has attracted a lot of interest as a potential target for the design of anticancer chemotherapies. Like cancer cells, protozoan parasites grow quickly and it is therefore likely that they need polyamines to survive. This hypothesis has led to the analyses of the polyamine metabolism of several protozoan parasites and this session will focus primarily on the significant differences that occur between the mammalian polyamine metabolism and those metabolic pathways occurring in a variety of protozoan parasites, including trypanosomatids and Plasmodium.
The aim of this session is to appreciate the differences of polyamine metabolism between host and protozoan parasites and to understand why this metabolic pathway offers potential for drug discovery against protozoan parasites
At the end of the session you should:
understand the roles of polyamines in parasites and in mammalian cells;
understand which enzymes are involved in the biosynthesis of polyamines and other
polyamine-linked metabolites;
know how chemicals/drugs interfere with polyamine metabolism;
understand the reasons for selective activity of polyamine biosynthesis inhibitors against t. brucei gambiense.
A list of recommended reading is provided on Moodle
Nguyen S, Jones DC, Wyllie S, Fairlamb AH, Phillips MA. (2013) Allosteric activation of trypanosomatid deoxyhypusine synthase by a catalytically dead paralog. J Biol Chem. 288(21):15256-67
Why and how and do trypanosomatids control and regulate their polyamine homeostasis?
What is the evidence for polyamine biosynthesis being a good target for chemotherapy in trypanosomatids?
What is hypusine and why is it important?
Describe Figure 1 and the conclusions drawn from this analysis.
Which experiments were performed to show that DHS is essential for survival of T. brucei in vitro and in vivo?
What is the evidence that DHSc and DHSp form a complex?
Describe how an immunoprecipitation is carried out and what controls you would include in this type of analysis?
How was it shown that DHSc/DHSp form a heterotetramer that is functional in T. brucei?
Is T. brucei DHS a potential target for drug discovery?
Helminth parasites cause great mortality and morbidity. A number of campaigns have been fought to reduce the burden of the diseases they cause but as yet they have had limited success. One exception is the near eradication of Guinea worm. In the last few years the control of helminths has come to depend on the widespread use of safe, relatively inexpensive, but highly effective drugs. Concerns over the emergence of drug-resistance remain and the vaccine development effort continues.
To inform you of the current global status of the soil-transmitted helminths, (Ancylostoma duodenale, Necator americanus, Ascaris lumbricoides and Trichuris trichiura), the filariases (Onchocerca volvulus, Wuchereria bancrofti, Dracunculus medinensis) and schistosomes (Schistosoma haematobium, S. mansoni, S. japonicum)
To inform you of past, current and future methods and strategies for helminth control
You will learn about:
the public health importance of soil transmitted helminths and schistosomes;
the role of humans and the impact of environmental modifications on the spread of infection;
the implications of helminth distributions for disease mortality and morbidity;
current tools (drugs and vaccines) and strategies for disease control;
the planning and implementation of control measures;
meeting the costs of control;
remaining problems and challenges.
You will be able to:
describe the public health significance of these helminths;
describe the main tools that are available for control;
outline how these control measures are used to minimise the impact of these parasites;
appreciate the problems of defining public health priorities and funding interventions.
A list of recommended reading is provided on Moodle
Eberhard ML et al. The peculiar epidemiology of Dracunculiasis in Chad. American Journal of Tropical Medicine and Hygiene 2014, 90, 61-70.
What are the unusual epidemiological features of guinea worm in Chad from 2010-2013? Do you think cases may have occurred before 2010?
What could be responsible for increased detection after this?
Based on Figure 9, describe the lifecycle of Dracunculus medinensis, both the standard and potential cycles. Explain why eating undercooked/raw fish may be considered a factor in transmission.
Explain the methods used to identify the specific species of guinea worm. Where does transmission seem to occur?
What is a possible explanation for the higher incidence of guinea worm in dogs? What morphological features can be used to identify Dracunculus?
Could wild animals be a source of infection and how could this be Tested/confirmed? What changes could be put in place to try to reduce transmission?
What may these behavioural changes help identify?
Helminths (worms) are a large group of parasitic organisms grouped as cestodes (tapeworms), nematodes, and trematodes (flukes). Helminths cause very significant morbidity and mortality in humans and animals, and economic losses in farmed animals. Soil-transmitted nematodes like human hookworm infection are a leading cause of anaemia and protein malnutrition, affecting ~740 million people. Cestodes like tapeworms cause economic loss in livestock, but are of major concern when they infect humans and cause neurocysticercosis and hydatid disease. The difficulties of vaccine development against metazoans like helminths will be discussed, with emphasis on new vaccines against hookworms and taenid cestodes.
Ectoparasites (insects and mites) cause significant economic losses through their interactions with livestock. Some successful vaccines have been generated that are active against specific ectoparasites of fish and cattle and the development of some of these vaccines will be discussed.
To review currently available vaccines against helminth diseases of humans and animals
To learn about vaccination strategies aimed at ectoparasites
At the end of this session, you should be able to:
discuss the difficulties in developing vaccines against metazoan parasites such as helminths;
give examples of anti-helminthic vaccines in development;
describe the vaccine efficacies obtained in recent trials of vaccines to taenid cestodes in animals and hookworm in humans;
describe the successes in vaccination against ectoparasites of cattle.
A list of recommended reading is provided on Moodle
Diemert DJ, Freire J, Valente V, Fraga CG, Talles F, Grahek S, et al. (2017) Safety and immunogenicity of the Na-GST-1 hookworm vaccine in Brazilian and American adults. PLoS Negl Trop Dis 11(5): e0005574. https://doi.org/10.1371/journal.pntd.0005574
Be sure to include the following areas in your presentation of the paper:
The phases in development (Phase I, IIa, IIb etc.) of a vaccine
Previous work leading to the development of Na-GST-1 as a hookworm vaccine for humans
The likely mechanism by which the authors hypothesis that the vaccine will induce parasite death or reduce worm fecundity
The primary and secondary objectives of the two arms of the study
A description of the study design
What was measured in the vaccinees and how it was measured
A brief summary of the safety findings, but focus more on the data on immunogenicity
A comparison of the immunogenicity to the vaccine seen in the two sites, and possible explanations
What you think the potential is for further development of this vaccine
What you think the challenges are for further development of this vaccine
Malaria remains the most serious parasitic disease of man, causing half a million deaths each year mainly in young children in Africa south of the Sahara. Despite much effort there is no effective vaccine. Malaria vaccines could target the pre-erythrocytic or erythrocytic parasite life-cycle stages. Transmission blocking vaccines are also under consideration. Recent vaccine trials have shown promising results and these will be discussed and evaluated.
To review the evidence for efficacy of current malaria candidate vaccines
At the end of this session, you should be able to:
describe recent progress in vaccine development for control of malaria;
discuss potential vaccines against pre-erythrocytic and asexual parasite stages, and those aimed at blocking transmission to mosquitoes;
describe the vaccine efficacies obtained in recent trials of the RTS,S antimalarial vaccine.
A list of recommended reading is provided on Moodle
RTS,S Clinical Trials Partnership (2014). Efficacy and Safety of the RTS,S/AS01 Malaria Vaccine during 18 Months after Vaccination: A Phase 3 Randomized, Controlled Trial in Children and Young Infants at 11 African Sites. PLOS Medicine 11(7), e1001685.
What stages of the malaria parasite are targetted by the RTS,S vaccine and what does the vaccine consist of?
What is the evidence that the adjuvant used in this vaccine important to its efficacy?
What was the objective of this study and what endpoints were measured?
What does ‘double-blinded, randomised, placebo-controlled’ mean? What was used as the placebo and why?
Why are there two different ages of children being vaccinated?
What is the difference between “Intention to Treat” (ITT) and “per protocol” – and why do you think the study split into these two groups?
How were children monitored for malaria infection? What definitions of malaria and severe malaria were used?
Does this vaccine work and what are the major effects (endpoints)?
Does the vaccine protect children against clinical malaria?
Does the vaccine protect children against severe malaria?
What do the 95% CI for the vaccine efficacy tell you?
Why are there differences in the efficacy of the vaccine in different countries?
Is there any evidence that the vaccine works differently in younger children (<24 months of age)? If so, why is that thought to be?
Do you think this vaccine should be introduced for malaria control in Africa?
Drug resistance is a major issue in the control of the protozoan infectious diseases. It can be achieved through a variety of molecular mechanisms including: 1) changes in drug influx into the cell, 2) active transport of drugs out of its place of action, 3) modification of the drug target so it is no longer recognized/inhibited by the compound 4) modification of the compound or block of its activation and 5) up-regulation of the repair mechanism, which allows the parasite to thrive despite the presence of the drug effects.
This session discusses the molecular basis of resistance to the most popular anti-kinetoplastid and antimalarial drugs and genetic background underlying it.
Presentation of the common paths by which the protozoan parasites acquire resistance and overview of the molecular mechanisms of resistance to commonly used antiparasitic compounds
At the end of the session you should be able to:
Understand and give examples of different ways parasites can acquire resistance to drugs
Understand the current view of the mechanisms of resistance to commonly used antimalarials (PYR, CQ, ART) and anti-kinetoplastid drugs (meralsopol, pentamidine, amphotericin B)
Know how the resistance is assessed and what strategies are commonly used to map the genes and proteins involved in this process.
A list of recommended reading will be provided on Moodle
Alex Rosenberg, Madeline R. Luth, Elizabeth A. Winzeler, Michael Behnke, L. David Sibley “Evolution of resistance in vitro reveals mechanisms of artemisinin activity in Toxoplasma gondii”, Proceedings of the National Academy of Sciences Dec 2019, 201914732;
What was the approach that the authors used to identify the ART resistance mechanisms in Toxoplasma?
Why the untreated parasite was passaged alongside of the ART-selected line?
What shared genetic changes were discovered in the two selected lines?
What the authors were expecting to see after introducing the mutations into the selected line? What actually happened (Fig. 2)?
What was the aim of the competition experiment of the resistant and sensitive parasite (Fig. 3) ? What did it show?
What authors discovered after examining the mitochondrial DNA? What did it mean for the ART resistance?
How authors assessed the mitochondrial functions in the sensitive and resistant parasites? What it did reveal?
What are the similarities and differences between the ART resistance in Plasmodium and Toxoplasma parasites according to the authors?
The appearance and spread of the resistance to antiprotozoal drugs is a complex phenomenon influenced by multiple host, parasite and environmental factors. The history of the first-line therapies directed towards the apicomplexan and kinetoplastid parasites shows that even a mild loss of efficiency can ultimately eliminate the drug from use globally. Therefore, a lot of effort goes into understanding what circumstances favor the development of the resistance, and adjusting the treatment regimens in a way that extends the longevity of both current and future drugs. The potential for resistance becomes also an important factor during the design of new compounds.
This lecture will discuss the mechanisms of evolution and spread of the resistance to anti-protozoan drugs (using both historical and contemporary examples) and the current strategies (eg combination therapy and resistance monitoring) used to control and delay it in the field.
Analysis of the mechanisms driving the evolution and spread of the resistance in the protozoan parasite population and the strategies used to prevent it.
At the end of the session you should:
Understand evolutionary pressures and mutation rates driving the appearance of resistance in the protozoan parasites
Be familiar with basic concepts required to understand the resistance dynamics eg. subcurative treatment, fitness cost, combination therapy etc.
Be able to explain how the probability of the resistance spread is impacted by: complexity of genetic background, fitness cost, parasite’s transmission intensity etc.
Know what features of potential drugs are making the appearance of resistance to them less likely.
A list of recommended reading will be provided on Moodle
Nina Wale, Derek G. Sim, Matthew J. Jones, Rahel Salathe, Troy Day and Andrew F. Read “Resource limitation prevents the emergence of drug resistance by intensifying within-host competition”, Proceedings of the National Academy of Sciences, December 26, 2017 114 (52) 13774-13779
Tsetse flies transmit African trypanosomes in sub-Saharan Africa. In Southern and central America reduviid bugs transmit Trypanosoma cruzi the causative agent of Chagas’ disease. Vector control offers an important means of controlling these diseases. A number of methods are in place including: spraying of insecticides (often in a targeted fashion to minimise affects on other species), the use of traps and the release of sterile males to induce non-productive mating. Tsetse flies have been cleared from the Island of Zanzibar, but efforts on mainland Africa have been impeded by logistical constraints. The Southern Cone initiative, and other initiatives in Southern and Central America, have had considerable success in reducing the burden of Chagas’ disease.
To describe and evaluate different methods of vector control against insects that transmit trypanosomes
At the end of this session, you should be able to:
discuss methods used in controlling tsetse flies;
discuss methods used in controlling reduviid bugs;
describe campaigns aimed at limiting the distribution of insect vectors of trypanosomes;
evaluate the evidence for the success of these methods.
A list of recommended reading is provided on Moodle
Since the discovery of the role of the Anopheles mosquitoes as vectors of malaria at the end of the nineteenth century, vector control has been an important method for the management of malaria. Residual spraying of houses with insecticide and insecticide-treated bednets are commonly used methods. In the future, genetic modification of mosquitoes may contribute to control measures.
To describe and evaluate different methods of vector control
At the end of this session, you should be able to:
discuss the evidence for efficacy of insecticide treated bednets, and household spraying with insecticide;
evaluate the potential of genetic modification of mosquitoes in malaria control;
describe the most appropriate method for vector control in different epidemiological situations.
A list of recommended reading is provided on Moodle
Akogbéto et al (2013) Six years of experience in entomological surveillance of indoor residual spraying against malaria transmission in Benin: lessons learned, challenges and outlooks. Malar J. 2015 Jun 12;14:242. doi: 10.1186/s12936-015-0757-5.
What are the four evaluations described in the paper?
Where were the trials carried out (and why did they change the trial site)?
Which insecticides were used, how were they chosen, and how do they work against mosquitoes?
How were adult mosquitoes sampled (two methods), and what did the authors investigate for the mosquitoes they caught with each method?
How was susceptibility to insecticides monitored during the study?
What was the effect of IRS spraying on mosquito biting frequency in the different sites, and throughout the trial period?
How long did the effect of IRS on biting rate last?
What was the impact of IRS on blood feeding of Anopheles gambiae?
Was there any increase in insecticide resistance during the period of the study?
What were the successes of the IRS intervention?
What were the main challenges they met during the study?
What challenges do the authors discuss for the use of IRS, and what solutions do they suggest?