The Fatty Acid Biosynthesis Enzyme FabI Plays a Key Role in the Development of Liver-Stage Malarial Parasites

Abstract

SUMMARY Fatty acid biosynthesis has been viewed as an important biological function of and therapeutic target for Plasmodium falciparum asexual blood stage infection. This apicoplast-resident type II pathway, distinct from the mammalian type I process, includes FabI. Here, we report synthetic chemistry and transfection studies concluding that Plasmodium FabI is not the target of the antimalarial activity of the bacterial FabI inhibitor triclosan. Disruption of fabI in P. falciparum or the rodent parasite P. berghei does not impede blood stage growth. In contrast, mosquito-derived fabI-deficient P. berghei sporozoites are markedly less infective for mice and typically fail to complete liver stage development in vitro. This is characterized by an inability to form intra-hepatic merosomes that normally initiate blood stage infections. These data illuminate key differences between liver and blood stage parasites in their requirements for host versus de novo synthesized fatty acids, and create new prospects for stage-specific antimalarial interventions.

Triclosan inhibit the growth of the late liver‐stage of Plasmodium

“…We hypothesize that fatty acid biosynthesis is one of the limiting factors in the liver-stage parasite growth. Our hypothesis is also supported by the recent findings (22,23).…”

“…The other enzymes of FAS-II pathway Fab B/F, and FabZ knockout in P. yoelii, lead to normal parasite (blood stage) development but completely fail to form infective merozoites during the liver-stage growth (22). These studies (22,23) also highlighted the importance of FAS-II pathway enzymes during the development of late liver-stage parasites as the early stages of liver parasites show normal development (22,23). Together FAS-II gene disruption data appear to make a compelling case for the importance of de novo fatty acid biosynthesis in the successful production of thousands of infectious merozoites produced per liver schizont.…”

“…Recently, Yu et al (23) showed the FabI deleted P. berghei liver-stage parasites were severely defective in the development of merozoite. The other enzymes of FAS-II pathway Fab B/F, and FabZ knockout in P. yoelii, lead to normal parasite (blood stage) development but completely fail to form infective merozoites during the liver-stage growth (22).…”

“…Zhou et al (21) predicted that the liver-stage parasites might also be prone to inhibitors that interfere with Type-II fatty acid biosynthesis. Recent knockout (of FAS-II enzymes) studies further support the importance of this pathway in the development of liver-stage parasites (22,23).…”

Phospholipases during membrane dynamics in malaria parasites

“…Plasmodium can also synthesize FAs de novo via the fatty acid synthase II (FASII) pathway located in the apicoplast, a relict plastid of algal origin that arose through secondary endosymbiosis (e.g reviewed in van Dooren and Striepen, 2013). FA synthesis via FASII, though, occurs primarily in the mosquito-resident and intrahepatic stages (van Schaijk et al, 2014;Vaughan et al, 2009;Yu et al, 2008).…”