Overcoming synthetic challenges in targeting coenzyme A biosynthesis with the antimicrobial natural product CJ-15,801

Domingo, Riyad; Westhuyzen, Renier van der; Hamann, Anton R.; Mostert, Konrad J; Barnard, Leanne; Paquet, Tanya; Tjhin, Erick T.; Saliba, Kevin J.; Otterlo, Willem A. L. van; Strauss, Erick

doi:10.1039/c9md00312f

Cited by 4 publications

(3 citation statements)

References 26 publications

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“…The test compounds used in this study were obtained as follows: Pan ( 1 ), (PantSH, 3 ), d ‐panthenol ( 4 ) and dL ‐pantoyltaurine sodium salt ( 7 ) were obtained from Sigma‐Aldrich (Merck, KGaA). P‐Pan ( 2 ) [14] and analogues 5 , [15] 6 , [1c] 8 , [16] 9 , [16] 10 , [9,17] 11 , [18] 12 , [18] and 14 [1c] were prepared according to the procedures reported in the indicated references. The synthetic procedures used to prepare compounds 13 , [19] 15 , 16 , [19] 17 [20] and 18 are described in the Supporting Information.…”

Section: Methodsmentioning

confidence: 99%

Multifaceted Target Specificity Analysis as a Tool in Antimicrobial Drug Development: Type III Pantothenate Kinases as a Case Study

et al. 2023

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The research and development of a new antimicrobial drug using a target‐based approach raises the question of whether any resulting hits will also show activity against the homologous target in other closely related organisms. While an assessment of the similarities of the predicted interactions between the identified inhibitor and the various targets is an obvious first step in answering this question, no clear and consistent framework has been proposed for how this should be done. Here we developed Multifaceted Target Specificity Analysis (MTSA) and applied it to type III pantothenate kinase (PanKIII) – an essential enzyme required for coenzyme A biosynthesis in a wide range of pathogenic bacteria – as a case study to establish if targeting a specific organism's PanKIII would lead to a narrow‐ or broad‐spectrum agent. We propose that MTSA is a useful tool and aid for directing new target‐based antimicrobial drug development initiatives.

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Section: Methodsmentioning

confidence: 99%

Multifaceted Target Specificity Analysis as a Tool in Antimicrobial Drug Development: Type III Pantothenate Kinases as a Case Study

et al. 2023

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“…However, the lack of an effective vaccine 3 and emerging drug-resistance against all available treatment regimens 4 highlight the need for new antimalaria strategies. Coenzyme A (CoA) biosynthesis has been shown to be an excellent target for antimalarial intervention [5][6][7][8] , largely because CoA is required for the formation of the central metabolite acetyl-CoA. Acetyl-CoA occupies a critical position in many metabolic processes including fatty acid biosynthesis, amino acid metabolism, and TCA cycle metabolism 9 .…”

Section: Introductionmentioning

confidence: 99%

The mitochondrion of Plasmodium falciparum generates essential acetyl-CoA for protein acetylation

Nair

Munro²,

Mann

et al. 2022

Preprint

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Coenzyme A (CoA) biosynthesis is an excellent target for antimalarial intervention. While most studies have focused on the use of CoA to produce acetyl-CoA in the apicoplast and the cytosol of malaria parasites, mitochondrial acetyl-CoA production is less well understood. In the current study, we performed metabolite labeling experiments to measure endogenous metabolites in Plasmodium falciparum lines with genetic deletions affecting mitochondrial dehydrogenase activity. Our results show that mitochondrial acetyl-CoA biosynthesis is essential for parasite growth and identify a catalytic redundancy between the two main ketoacid dehydrogenase enzymes, both of which are able to produce acetyl-CoA. The activity of these enzymes is dependent on the lipoate attachment enzyme LipL2, which is essential for parasite survival solely based on its role in supporting acetyl-CoA metabolism. We also find that acetyl-CoA produced in the mitochondrion is essential for the acetylation of histones and other proteins outside of the mitochondrion. Taken together, our results demonstrate that the mitochondrion is an essential de novo source of acetyl-CoA and is required for P. falciparum protein acetylation critical to parasite survival.

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“…Emerging drug resistance against all available malaria treatment regimens ( 1 ) highlights the need for new antimalaria strategies. Coenzyme A (CoA) biosynthesis has been shown to be an excellent target for antimalarial intervention ( 2 – 5 ), largely because CoA is required for the formation of the central metabolite acetyl-CoA. Acetyl-CoA occupies a critical position in many metabolic processes including fatty acid biosynthesis, amino acid metabolism, and TCA cycle metabolism ( 6 ).…”

mentioning

confidence: 99%

The mitochondrion of Plasmodium falciparum is required for cellular acetyl-CoA metabolism and protein acetylation

Nair

Munro

Mann

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Coenzyme A (CoA) biosynthesis is an excellent target for antimalarial intervention. While most studies have focused on the use of CoA to produce acetyl-CoA in the apicoplast and the cytosol of malaria parasites, mitochondrial acetyl-CoA production is less well understood. In the current study, we performed metabolite-labeling experiments to measure endogenous metabolites in Plasmodium falciparum lines with genetic deletions affecting mitochondrial dehydrogenase activity. Our results show that the mitochondrion is required for cellular acetyl-CoA biosynthesis and identify a synthetic lethal relationship between the two main ketoacid dehydrogenase enzymes. The activity of these enzymes is dependent on the lipoate attachment enzyme LipL2, which is essential for parasite survival solely based on its role in supporting acetyl-CoA metabolism. We also find that acetyl-CoA produced in the mitochondrion is essential for the acetylation of histones and other proteins outside of the mitochondrion. Taken together, our results demonstrate that the mitochondrion is required for cellular acetyl-CoA metabolism and protein acetylation essential for parasite survival.

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Overcoming synthetic challenges in targeting coenzyme A biosynthesis with the antimicrobial natural product CJ-15,801

Abstract: Presenting an optimised synthesis of the fungus-derived antibiotic CJ-15,801 which shows selective activity against Staphylococcus aureus and Plasmodium falciparum.

Cited by 4 publications

References 26 publications

Multifaceted Target Specificity Analysis as a Tool in Antimicrobial Drug Development: Type III Pantothenate Kinases as a Case Study

Multifaceted Target Specificity Analysis as a Tool in Antimicrobial Drug Development: Type III Pantothenate Kinases as a Case Study

The mitochondrion of Plasmodium falciparum generates essential acetyl-CoA for protein acetylation

The mitochondrion of Plasmodium falciparum is required for cellular acetyl-CoA metabolism and protein acetylation

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