Beyond the MEP Pathway: A novel kinase required for prenol utilization by malaria parasites

Crispim, Marcell; Verdaguer, Ignasi Bofill; Hernández, Agustín; Kronenberger, Thales; Fenollar, Àngel; Yamaguchi, Lydia Fumiko; Alberione, María Pía; Ramirez, Miriam; de Oliveira, Sandra Souza; Katzin, Alejandro Miguel; Izquierdo, Luis

doi:10.1371/journal.ppat.1011557

Cited by 3 publications

References 92 publications

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Validation of DXS as an attractive drug target in mycobacteria

Maila,

Nicolaai,

Mbau

et al. 2024

Preprint

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A rapid emergence in the incidences of Tuberculosis (TB) drug resistance undermines efforts to eradicate the disease and strengthens calls for development of new drugs with novel mechanisms of action. In drug discovery, finding an attractive drug target is as important as finding a good drug candidate. Hence more efforts are made to identify, validate and prioritize drug targets in TB drug discovery. Here, using CRISPRi technology, we showed that dxs1 transcriptional knockdown attenuated growth of both Mycobacterium smegmatis and Mycobacterium tuberculosis cultures, and the effect was more profound in the latter. Chemical supplementation of the growth medium with 10 uM of isoprenoid pyrophosphates, thiamine and thiamine pyrophosphate failed to rescue growth of M. smegmatis cultures, while partial rescue was observed with addition of menatetrenone, a menaquinone derivative with four isoprenyl groups. Similarly, culture growth could not be rescued by the addition of prenol and isoprenol, which suggested the lack of isoprenoid salvage pathway in mycobacteria. Importantly, and in the context of drug discovery, dxs1 depleted mutants displayed four-fold more sensitive towards a mixture of isoniazid, rifampicin and ethambutol, suggesting that inhibitors of DXS1 or other MEP pathway enzymes could potentiate antimycobacterial effect of the first-line TB drugs. Additionally, dxs1 depletion increased growth retardation of the mutant in acidic pH and under oxidative stress, conditions that are encountered in activated macrophage compartments. Taken together, our results validated DXS1 as an attractive drug target that should be prioritized for developments on new antitubercular agents.

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Validation of DXS as an attractive drug target in mycobacteria

Maila,

Nicolaai,

Mbau

et al. 2024

Preprint

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Absence of farnesol salvage in Candida albicans and probably in other fungi

Voshall,

Gutzmann,

Verdaguer

et al. 2024

Appl Environ Microbiol

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Farnesol salvage, a two-step pathway converting farnesol to farnesyl pyrophosphate (FPP), occurs in bacteria, plants, and animals. This paper investigates the presence of this pathway in fungi. Through bioinformatics, biochemistry, and physiological analyses, we demonstrate its absence in the yeasts Saccharomyces cerevisiae and Candida albicans , suggesting a likely absence across fungi. We screened 1,053 fungal genomes, including 34 from C. albicans , for potential homologs to four genes ( Arabidopsis thaliana AtFOLK , AtVTE5 , AtVTE6 , and Plasmodium falciparum PfPOLK ) known to accomplish farnesol/prenol salvage in other organisms. Additionally, we showed that 3 H-farnesol was not converted to FPP or any other phosphorylated prenol, and exogenous farnesol was not metabolized within 90 minutes at any phase of growth and did not rescue cells from the toxic effects of atorvastatin, but it did elevate the levels of intracellular farnesol (F i ). All these experiments were conducted with C. albicans . In sum, we found no evidence for farnesol salvage in fungi. IMPORTANCE The absence of farnesol salvage constitutes a major difference in the metabolic capabilities of fungi. In terms of fungal physiology, the lack of farnesol salvage pathways relates to how farnesol acts as a quorum-sensing molecule in Candida albicans and why farnesol should be investigated for use in combination with other known antifungal antibiotics. Its absence is essential for a model (K. W. Nickerson et al., Microbiol Mol Biol Rev 88:e00081-22, 2024), wherein protein farnesylation, protein chaperones, and the unfolded protein response are combined under the unifying umbrella of a cell’s intracellular farnesol (F i ). In terms of human health, farnesol should have at least two different modes of action depending on whether those cells have farnesol salvage. Because animals have farnesol salvage, we can now see the importance of dietary prenols as well as the potential importance of farnesol in treating neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and multiple sclerosis.

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Apicoplast-Resident Processes: Exploiting the Chink in the Armour of Plasmodium falciparum Parasites

Mamudu,

Tebamifor,

Sule

et al. 2024

Advances in Pharmacological and Pharmaceutical Sciences

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The discovery of a relict plastid, also known as an apicoplast (apicomplexan plastid), that houses housekeeping processes and metabolic pathways critical to Plasmodium parasites’ survival has prompted increased research on identifying potent inhibitors that can impinge on apicoplast-localised processes. The apicoplast is absent in humans, yet it is proposed to originate from the eukaryote’s secondary endosymbiosis of a primary symbiont. This symbiotic relationship provides a favourable microenvironment for metabolic processes such as haem biosynthesis, Fe-S cluster synthesis, isoprenoid biosynthesis, fatty acid synthesis, and housekeeping processes such as DNA replication, transcription, and translation, distinct from analogous mammalian processes. Recent advancements in comprehending the biology of the apicoplast reveal it as a vulnerable organelle for malaria parasites, offering numerous potential targets for effective antimalarial therapies. We provide an overview of the metabolic processes occurring in the apicoplast and discuss the organelle as a viable antimalarial target in light of current advances in drug discovery. We further highlighted the relevance of these metabolic processes to Plasmodium falciparum during the different stages of the lifecycle.

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Beyond the MEP Pathway: A novel kinase required for prenol utilization by malaria parasites

Cited by 3 publications

References 92 publications

Validation of DXS as an attractive drug target in mycobacteria

Validation of DXS as an attractive drug target in mycobacteria

Absence of farnesol salvage in Candida albicans and probably in other fungi

Apicoplast-Resident Processes: Exploiting the Chink in the Armour of Plasmodium falciparum Parasites

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