Biology subjects

Ben Mamoun, C.

Publications and source records attributed to Ben Mamoun, C..

3 recordsLinked to original sources

bioRxiv2023

Spermidine Is The Main Polyamine Required By Intracellular Parasites For Survival Within Host Erythrocytes

Intracellular eukaryotic pathogens such as Babesia and Plasmodium, the agents of human babesiosis and malaria, require salvage or de novo synthesis of several nutrients for survival in human erythrocytes. One such nutrient is putrescine, which is either transported from the host or synthesized from ornithine and serves as a precursor for the biosynthesis of two other polyamines: spermidine and spermine. However, the specific polyamines required by these parasites for survival and the molecular process they control remain unknown. We show in both B. duncani and P. falciparum that spermidine is the main product of the polyamine biosynthesis machinery required for parasite survival. Simultaneous inhibition of spermidine synthesis from putrescine and catabolism from spermine results in cell death and parasite survival can only be rescued by spermidine. Finally, we demonstrate that spermidines essential function in these parasites is through regulation of protein translation via hypusination of the translation initiation factor eIF5A.

microbiology↗

bioRxiv2022

Decoding The Nuclear Genome of The Human Pathogen Babesia duncani Shed Light on its Virulence, Drug Susceptibility and Evolution among Apicomplexa

Babesia species are tick-transmitted apicomplexan pathogens and the causative agents of babesiosis, a malaria-like disease of major medical and veterinary importance. Of the different species of Babesia reported so far, Babesia duncani causes severe to lethal infection in patients. Despite the highly virulent nature of this parasite and the risk it may pose as an emerging pathogen, little is known about its biology, metabolic requirements, and pathogenesis. B. duncani is unique among apicomplexan parasites that infect red blood cells in that it can be continuously cultured in vitro in human erythrocytes but can also infect mice leading to fulminant babesiosis infection and death. Here we have taken advantage of the recent advances in the propagation of this parasite in vitro and in vivo to conduct detailed molecular, genomic and transcriptomic analyses and to gain insights into its biology. We report the assembly, 3D structure, and annotation of the nuclear genome of this parasite as well as its transcriptomic profile and an atlas of its metabolism during its intraerythrocytic life cycle. Detailed examination of the B. duncani genome and comparative genomic analyses identified new classes of candidate virulence factors, suitable antigens for diagnosis of active infection, and several attractive drug targets. Translational analyses and efficacy studies identified highly potent inhibitors of B. duncani thus enriching the pipeline of small molecules that could be developed as effective therapies for the treatment of human babesiosis.

microbiology↗

bioRxiv2021

Effective Therapy Targeting Cytochrome bc1 Prevents Babesia Erythrocytic Development and Protects from Lethal Infection

Targeting conserved metabolic processes that are essential for viability of pathogens, such as Plasmodium and Babesia that cause blood-borne diseases, is an effective strategy to eliminate malaria and babesiosis infections with no recrudescence. One interesting target is the mitochondrial cytochrome bc1 complex, which could be inhibited by drugs such as endochin-like quinolones (ELQ) and atovaquone. We used the tick-transmitted and culturable blood-borne pathogen Babesia duncani to evaluate the structure-activity relationship, safety, efficacy and mode of action of ELQs. We identified a potent and highly selective ELQ prodrug (ELQ-502), which alone or in combination with atovaquone eliminates B. microti and B. duncani infections in vitro and in mouse models of parasitemia and lethal infection. The strong efficacy at low dose, excellent safety, bioavailability and long half-life of this experimental therapy makes it an ideal clinical candidate for the treatment of human infections caused by Babesia and its closely related apicomplexan parasites.

microbiology↗