Using model organisms to facilitate advances in medical parasitology

Question 1

LO

Answer 1

• The learning outcomes for this part of the module are related to pharmacological strategies for parasite control.
• After studying this topic, the lecture and recommended reading you should be able to:
• Understand the core processes for drug discovery in medical parasitology
• Critically evaluate the use of model genetic organisms for the study of parasitic helminths.

Question 2

What are some of the challenges that need to be addressed with medical parasitology?

Answer 2

Population-based chemotherapy programmes

Complex life cycles; intimate association with human host

Emerged and emerging anthelmintic resistance

Low-cost therapies
i.e., the need the safe, broad spectrum, resistance-breaking, low-cost novel nematicidal drugs

Question 3

Target site for currently used anthelmintics

Answer 3

Question 4

With the experimental routes to new drugs like Phenotypic-based screening, what can this be tested on and what effect is seen?

Answer 4

Question 5

Name some good model organisms

Answer 5

C. elegans

Ascaris suum

These are both nematode round worms

Question 6

Why are model organisms used when testing out new drugs?

Answer 6

• Easy (and cheap) to culture and maintain in the lab
• Phylogenetically related
• Conserved neurobiology
• (very) genetically tractable
• Suitable for high-throughput chemical screening
• Suitable for delineating mode of action

Question 7

Tell me how they are easy (and cheap) to culture and maintain in the lab

Answer 7

Question 8

How are nematodes phylogenetically related?

Answer 8

Question 9

What may be used to evaluate drug targets in parasitic species in the future?

Answer 9

‘model hopping’

Question 10

What needs to be done for ‘model hopping’?

Answer 10

identify gene of interest in parasitic nematode

identify orthologous gene in C. elegans

obtain phenotype of C. elegans mutant e.g. drug resistance

generate transgenic C. elegans expressing the parasitic gene and test whether this reinstates sensitivity to the drug

Question 11

Suitable for high-throughout chemical screening

Answer 11

Question 12

How are model organisms suitable for delineating mode of action?

Answer 12

Ivermectin receptor

Benzimidazole mode of action

Levamisole receptor

Emodepside receptor*

*Guest et al. 2007 on BB, extra reading

… and mechanisms of resistance…

Question 13

What are the two main mechanisms for delineating the mode of action?

Answer 13

Mutations in drug targets

Detoxification

Question 14

What are the limitations to the model organism approach?

Answer 14

Question 16

nAChR genes present in C.elegans and parasitic nematodes

Answer 16

Question 17

What is in site for the future?

Answer 17

Question 18

Summary

Answer 18

• provides insight into parasitic nematode biology
• provides a route to discover and characterise drug targets
• provides a platform to understand resistance
• but
• it is not always a reliable indicator