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Possible fungicidal activity of series 4 opensourcemalaria compounds? #8

Open MFernflower opened 6 years ago

MFernflower commented 6 years ago

I have recently found a paper that states that fungal and malaria ion pumps are similar in structure and that malaria drugs targeting that pathway (Cipargamin) might also kill infectious fungi.
https://doi.org/10.1016/j.bbamem.2010.07.009

This paper is backed up by and references a study that shows C. neoformans was non-infectious when it's pfatp4 homologue was disabled by genetic modification: http://ec.asm.org/content/8/3/315

"A screen of 10% of the strain collection in mice identified an avirulent mutant strain with an insertion in the ENA1 gene, which is predicted to encode a fungus-specific sodium or potassium P-type ATPase. The results of the deletion of the gene and complementation experiments confirmed its key role in mammalian virulence. ena1 mutant strains exhibited no change in sensitivity to high salt concentrations but were sensitive to alkaline pH conditions, providing evidence that the fungus may have to survive at elevated pH during infection of the mammalian host. "

My question for the community is as follows: Do you think it is worth sending 2 potent and 2 inactive OpenSourceMalaria S4 malaria compounds for testing against Maduramycosis?

wwjvdsande commented 6 years ago

I think this is a good suggestion, although taken with a little bit caution. Cryptococcus is genetically seen very distinct from other pathogenic fungi such as the mycetoma causative agents. So it might be that the compounds might not inhibit Madurella mycetomatis too. On the other hand, if we don't test it, we will not know.

MFernflower commented 6 years ago

@david1597 when you get the chance can you mull this over with the rest of the (malaria) team in Sydney?

I'm particularly interested in getting the LHS cubane tested against Madurella (because of the high logp)

MFernflower commented 6 years ago

@wwjvdsande how many milligrams of compound is needed per study?

wwjvdsande commented 6 years ago

It depends on the concentration you think it is active. For most compounds for in vitro testing only it would take around 10 mg.

MFernflower commented 5 years ago

S4 and S3 drugs found inactive against yeast @wwjvdsande https://github.com/OpenSourceMalaria/Series4/issues/64 @mattodd I still feel this would be good to run as we can screen against fliamentous fungi since the coadd assay only says S4 & S3 ineffective against yeast