Leishmaniose
new drugs in the pipeline
(mechanisms)
by Peter Krüger
What is Leishmaniose?
 protozoan infectious disease
 obligate intracellular
 disease of the poor
 affects humans and animals
 visceral / cutaneous /
mucocutaneous
Canine vector-borne diseases in Brazil; Parasites & Vectors, 2008, Volume 1, Number 1, Page 25; Filipe DantasTorres
Epidemiology of Leishmaniosis
mci-forum.com/clinical-and-epidemiological-assessment-in-visceral-leishmaniasis
Recent Treatments
 Pentavalent Antimonials
 Sitamaquine
 Amphotericin B
 Pentamidine
 Miltefosin
 Aromomycin
images.rxlist.com
Disadvantages:
 toxic
 costly
 ineffective due to resistance
Croft et. al; “Drug Resistance in Leishmaniasis.” Clinical Microbiology Reviews 2006
Requirements for future Antileishmania Drugs




less toxic
no resistance of Leishmania against the drug
cheap
target Leishmania specific enzymes/ structures
mynewsla.com
New potential Targets
Polyamine Biosynthesis
 Polyamins play role in
differentiation and growth of
parasite
 Polyamin pool is strictly regulated
 Drug targets that are involved in
polyamine level
regulation(LmPOT1)
Martin C. Taylor et al.; Biochemical journal; 2008
New potential Targets
Peptidases
 Peptidase inhibitors in HIV,
hypertension and multiple
myeloma treatment
 154 peptidases in Leishmania
 Proteasome as potencial drug
target
 CPB works as virulence factor
Besteiro, Sébastien et al; Molecular microbiology 2016.
New potential Targets
Glycosomal Machinery
 Host as the carbon sorce of the
Leishmania parasite
 Uptake of blood glucose, fatty
acids, amino acids
 Parasite glycosome
 Glycolysis causes development
of superoxides
Mittra, Bidyottam, and Norma W. Andrews; Trends in parasitology 2016
New potential Targets
Thiol Metabolism
 Parasites escape reactive oxygen and nitrogen species
 Antioxidant enzymes [T(SH)2]
 Differences in mammalian GST and parasitic TR  possible targets
Wyllie, Susan, Tim J. Vickers, and Alan H. Fairlamb; Antimicrobial Agents and Chemotherapy 2016
New potential Targets
Cyclin dependent Kinanses
 Importance in cell division, differentiation, transcription and apoptosis
 Target these kinases (CRK3 = cdk related kinase 3)
 Reduced viability of parasite
New potential Targets
MAPK pathway
 affects cell growth and differentiation
 Important for every Leishmania life cycle
 new targets for treatment when parasite specific MAPK sequences are found
Michael J. Brumlik et al.; Journal of Signal Transduction2011.
New potential Targets
Sterol Biosynthesis
 mainly ergosterol and stigmasterol – different
from mammalian cholesterol
 Azosterol  impact on ergosterol
biosynthesis(C14DM)
 Leishmania survives in altered sterol
environment  combinational therapy
Xu W, Hsu F-F, Baykal E, Huang J, Zhang K (2014) PLoS
New potential Targets
DHFR
 key enzyme in folate metabolism
 no thymidine production
 no DNA biosynthesis
Ian H Gilbert; 2002.
Leishmania vaccine
 Not yet available due to parasite
complexity
 Canine vaccinces available in
Brazil
 Proteomics discover new
potencial targets
 Herbal drugs help to increase
hosts immune response
 Half a dozen vaccines in the
pipeline
solutionscanines-blog.com/wordpress/la-leishmaniose-canine
Leishmania vaccine
Joshi Sumit et. al; Frontiers in Immunology ; 2014
New Treatsments aim at different stages of the
Leishmania life cycle
www.niaid.nih.gov
Thank you for your Attention
REFERENCES:
Primary References:
Canine vector-borne diseases in Brazil; Parasites & Vectors, 2008, Volume 1, Number 1, Page 25; Filipe Dantas-Torres
Croft, Simon L., Shyam Sundar, and Alan H. Fairlamb. “Drug Resistance in Leishmaniasis.” Clinical Microbiology Reviews 19.1 (2006): 111–126. PMC. Web. 11 June 2016.
Besteiro, Sébastien, Graham H. Coombs, and Jeremy C. Mottram. “A Potential Role for ICP, a Leishmanial Inhibitor of Cysteine Peptidases, in the Interaction between Host and Parasite.”
Molecular microbiology 54.5 (2004): 1224–1236. PMC. Web. 11 June 2016.
Mittra, Bidyottam, and Norma W. Andrews. “IRONy OF FATE: Role of Iron-Mediated ROS in Leishmania Differentiation.” Trends in parasitology 29.10 (2013): 489–496. PMC. Web. 11 June 201
Wyllie, Susan, Tim J. Vickers, and Alan H. Fairlamb. “Roles of Trypanothione S-Transferase and Tryparedoxin Peroxidase in Resistance to Antimonials .” Antimicrobial Agents and Chemotherapy
52.4 (2008): 1359–1365. PMC. Web. 11 June 2016.
Michael J. Brumlik, Srilakshmi Pandeswara, Sara M. Ludwig, Kruthi Murthy, and Tyler J. Curiel, “Parasite Mitogen-Activated Protein Kinases as Drug Discovery Targets to Treat Human Protozoan
Pathogens,” Journal of Signal Transduction, vol. 2011, Article ID 971968, 16 pages, 2011. doi:10.1155/2011/971968
Xu W, Hsu F-F, Baykal E, Huang J, Zhang K (2014) Sterol Biosynthesis Is Required for Heat Resistance but Not Extracellular Survival in
Leishmania; PLoS; Pathog 10(10): e1004427. doi:10.1371/journal.ppat.1004427
Xu W, Hsu F-F, Baykal E, Huang J, Zhang K (2014) Sterol Biosynthesis Is Required for Heat Resistance but Not Extracellular Survival in Leishmania. PLoS Pathog 10(10): e1004427.
doi:10.1371/journal.ppat.1004427
Joshi Sumit et. al; Visceral Leishmaniasis: Advancements in vaccine development via classical and molecular approaches Frontiers in Immunology ; 2014
10.3389/fimmu.2014.00380
http://www.niaid.nih.gov/topics/leishmaniasis/pages/lifecycle.aspx
Internet Sources:
http://www.mci-forum.com/clinical-and-epidemiological-assessment-in-visceral-leishmaniasis/
http://mynewsla.com/wp-content/uploads/2015/05/sand-fly.jpg
http://oregonstate.edu/instruction/bi314/fall11/cellcycle.html
http://www.jubileevetcentre.co.uk/wp-content/uploads/2015/04/Map-Leishmaniosis-1024x844.jpg