Exploiting the coenzyme A biosynthesis pathway for the identification of new antimalarial agents: the case for pantothenamides

Abstract

Malaria kills more than half a million people each year. There is no vaccine, and recent reports suggest that resistance is developing to the antimalarial regimes currently recommended by the World Health Organization. New drugs are therefore needed to ensure malaria treatment options continue to be available. The intra-erythrocytic stage of the malaria parasite's life cycle is dependent on an extracellular supply of pantothenate (vitamin B5), the precursor of CoA (coenzyme A). It has been known for many years that proliferation of the parasite during this stage of its life cycle can be inhibited with pantothenate analogues. We have shown recently that pantothenamides, a class of pantothenate analogues with antibacterial activity, inhibit parasite proliferation at submicromolar concentrations and do so competitively with pantothenate. These compounds, however, are degraded, and therefore rendered inactive, by the enzyme pantetheinase (vanin), which is present in serum. In the present mini-review, we discuss the two strategies that have been put forward to overcome pantetheinase-mediated degradation of pantothenamides. The strategies effectively provide an opportunity for pantothenamides to be tested in vivo. We also put forward our 'blueprint' for the further development of pantothenamides (and other pantothenate analogues) as potential antimalarials.

Modular Enzymatic Cascade Synthesis of Vitamin B5 and Its Derivatives

“…An interesting class of new antimicrobials that target CoA biosynthesis is constituted by pantothenamides (PanAms), which are secondary or tertiary amides of pantothenic acid (vitamin B 5 , 5 a , Figure ), the biosynthetic precursor of CoA. Various PanAms have been shown to possess potent antimicrobial activity against several organisms, including the pathogenic bacterium Staphylococcus aureus as well as the malaria parasite Plasmodium falciparum . However, pantetheinase enzymes that normally hydrolyze pantetheine in human serum also act on the PanAms, thereby reducing their efficacy .…”

“…Various PanAms have been shown to possess potent antimicrobial activity against several organisms, including the pathogenic bac-terium Staphylococcus aureus [3] as well as the malaria parasite Plasmodium falciparum. [4] However, pantetheinase enzymes that normally hydrolyze pantetheinei nh uman serum also act on the PanAms,thereby reducing their efficacy. [5,6] Interestingly, pantetheinase-mediated hydrolysis of PanAms could be preventedb ym odifying the b-alaninem oiety of the compounds.…”

Coenzyme A and its derivatives: renaissance of a textbook classic

“…Three presentations addressed this topic: Kevin Saliba explored the potential for developing anti-malarial compounds targeting CoA biosynthesis in Plasmodium species [37], Joost Schalkwijk discussed chemical biology tools for vanin inhibition [10], and Erik Strauss outlined the structural and mechanistic differences between bacterial and human CoA biosynthetic enzymes which identify specific proteins as targets for antimicrobial drug discovery [9]. Three presentations addressed this topic: Kevin Saliba explored the potential for developing anti-malarial compounds targeting CoA biosynthesis in Plasmodium species [37], Joost Schalkwijk discussed chemical biology tools for vanin inhibition [10], and Erik Strauss outlined the structural and mechanistic differences between bacterial and human CoA biosynthetic enzymes which identify specific proteins as targets for antimicrobial drug discovery [9].…”

Biological characterization of chemically diverse compounds targeting the Plasmodium falciparum coenzyme A synthesis pathway

“…Recently, pantothenamides (secondary or tertiary amides of pantothenic acid) were shown to inhibit P. falciparum proliferation with sub-micromolar activity, but only when the serum enzyme pantetheinase is inhibited [17]. Currently, different strategies are being developed to overcome pantetheinase-mediated degradation of pantothenamides, thereby improving the activity of this group of pantothenic acid analogs in vivo [18–21]. …”