Amelioration of Cryptosporidium parvum Infection In Vitro and In Vivo by Targeting Parasite Fatty Acyl-Coenzyme A Synthetases

摘要: Cryptosporidium parvum is a unicellular zoonotic pathogen that can cause severe watery diarrhea in both humans and animals [1]. It emerging as 1 of the 4 top diarrheal pathogens children <5 years old developing countries [2]. Cryptosporidial infections immunocompromised individuals be prolonged life-threatening. In United States however, Food Drug Administration–approved treatments remain unavailable to treat this opportunistic infection patients with AIDS, whereas only nitazoxanide approved for use immunocompetent individuals. Therefore, there an urgent need new drugs, particularly those safely used persons. The slow progress anticryptosporidial drugs largely related unique metabolic features parasite, which are represented by highly streamlined metabolism inability synthesize nutrients de novo [3, 4]. This parasite has completely lost plastid-derived apicoplast present many other apicomplexans, remnant mitochondrion lacks citrate cycle cytochrome-based respiratory chain. classic drug targets Cryptosporidium, novel identified development. However, essential core pathways, including energy lipid synthesis parasite. Many enzymes within these pathways may serve because they either absent in, or divergent from animals. Within metabolism, adenosine monophosphate (AMP)-binding long-chain (LC) very fatty acyl coenzyme A (CoA) synthetases (ACSs; also known acid-CoA ligases [ACLs]; EC 6.2.1.3) large family catalyze thioesterification between free acids CoA form acyl-CoAs via 2-step reaction (Figure ​(Figure11A) [5]. ACS function acid transporters some organisms [6, 7]. indispensible all organisms, have activated acyl-CoA thioesters before enter various catabolic anabolic pathways. Fatty key intermediates biosynthesis cellular lipids β-oxidation [8]. Additionally, involved biological processes such protein modification [9, 10], cell proliferation [11], intracellular transport [12], signaling [13, 14]. Figure 1. Activation long chain acyl-coenzyme synthetase (ACS). A, Illustration ACS-catalyzed acid, triphosphate (ATP) reduced (HSCoA). ... The C. genome encodes 3 LC-ACSs (CpACS1, CpACS2, CpACS3), differs Plasmodium falciparum, at least 11 genes [15]. current study, we successfully expressed recombinant CpACS1 CpACS2 enzymatically active, maltose-binding (MBP) fusions, assayed their detailed enzyme kinetics. We demonstrated triacsin C, potent inhibitor, not could inhibit CpACS activity but was efficacious against growth, culture mice.