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© Jean-Claude Antoine
Leishmania mexicana amazonensis
Publication : Molecular microbiology

Probing druggability and biological function of essential proteins in Leishmania combining facilitated null mutant and plasmid shuffle analyses

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Molecular microbiology - 03 Jun 2014

Dacher M, Morales MA, Pescher P, Leclercq O, Rachidi N, Prina E, Cayla M, Descoteaux A, Späth GF

Link to Pubmed [PMID] – 24823804

Mol. Microbiol. 2014 Jul;93(1):146-66

Leishmania parasites cause important human morbidity and mortality. Essential Leishmania genes escape genetic assessment by loss-of-function analyses due to lethal null mutant phenotypes, even though these genes and their products are biologically most significant and represent validated drug targets. Here we overcome this limitation using a facilitated null mutant approach applied for the functional genetic analysis of the MAP kinase LmaMPK4. This system relies on the episomal expression of the target gene from vector pXNG that expresses the Herpes simplex virus thymidine kinase gene thus rendering transgenic parasites susceptible for negative selection using the antiviral drug ganciclovir. Using this system we establish the genetic proof of LmaMPK4 as essential kinase in promastigotes. LmaMPK4 structure/function analysis by plasmid shuffle allowed us to identify regulatory kinase sequence elements relevant for chemotherapeutic intervention. A partial null mutant, expressing an MPK4 derivative with altered ATP-binding properties, showed defects in metacyclogenesis, establishing a first link of MPK4 function to parasite differentiation. The approaches presented here are broadly applicable to any essential gene in Leishmania thus overcoming major bottlenecks for their functional genetic analysis and their exploitation for structure-informed drug development.

https://www.ncbi.nlm.nih.gov/pubmed/24823804