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allied
academies
J Pharmacol Ther Res 2017 Volume 1 Issue 2
November 02-03, 2017 Chicago, USA
4
th
International Congress on
International Conference and Exhibition on
Drug Discovery, Designing and Development
Biochemistry, Molecular Biology: R&D
&
T
he malaria parasite
Plasmodium falciparum
and related
apicomplexan pathogens contain an essential plastid
organelle, the apicoplast, which is a key anti-parasitic target.
Derived from secondary endosymbiosis, the apicoplast
depends on novel, but largely cryptic, mechanisms for
protein/lipid import and organelle inheritance during
parasite replication. These critical biogenesis pathways
present untapped opportunities to discover new parasite-
specific drug targets. We used an innovative screen to
identify actinonin as having a novel mechanism-of action
inhibiting apicoplast biogenesis. Resistant mutation,
chemical-genetic interaction, and biochemical inhibition
demonstrate that the unexpected target of actinonin in
P. falciparum
and
Toxoplasma gondii
is FtsH1, a homolog
of a bacterial membrane AAA+ metalloprotease. P
f
FtsH1
is the first novel factor required for apicoplast biogenesis
identified in a phenotypic screen. Our findings demonstrate
that FtsH1 is a novel and, importantly, druggable antimalarial
target. Development of FtsH1 inhibitors will have significant
advantages with improved drug kinetics and multistage
efficacy against multiple human parasites.
e:
katieambergjohnson@gmail.comSmall molecule inhibition of apicomplexan FtsH1 disrupts plastid biogenesis in human pathogens
Katherine Amberg-Johnson
Stanford University, USA