8s65

Publication Abstract from PubMed

Toxoplasma gondii is a widely distributed apicomplexan parasite causing toxoplasmosis, a critical health issue for immunocompromised individuals and for congenitally infected foetuses. Current treatment options are limited in number and associated with severe side effects. Thus, novel anti-toxoplasma agents need to be identified and developed. 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) is considered the rate-limiting enzyme in the non-mevalonate pathway for the biosynthesis of the isoprenoid precursors isopentenyl pyrophosphate (IPP) and dimethylallyl diphosphate (DMAPP) in the parasite, and has been previously investigated for its key role as a novel drug target in some species, encompassing Plasmodia, Mycobacteria and E. coli. In this study, we present the first crystal structure of T. gondii DXR (TgDXR) in a tertiary complex with the inhibitor fosmidomycin and the cofactor NADPH in dimeric conformation at 2.5 A resolution revealing the inhibitor binding mode. In addition, we biologically characterize alpha-phenyl-ss-thia and -oxa reverse fosmidomycin analogues and show that some derivatives are strong inhibitors of TgDXR which also, in contrast to fosmidomycin, inhibit the growth of T. gondii in vitro. Here, ((3,4-dichlorophenyl)((2-(hydroxy(methyl)amino)-2-oxoethyl)thio)methyl)phosphonic acid was identified as the most potent anti T. gondii compound. These findings will enable the future design and development of more potent anti-toxoplasma DXR inhibitors.

1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) as target for anti Toxoplasma gondii agents: crystal structure, biochemical characterisation and biological evaluation of inhibitors.,Mazzone F, Hoeppner A, Reiners J, Gertzen CGW, Applegate V, Abdullaziz MA, Gottstein J, Degrandi D, Wesemann M, Kurz T, Smits SH, Pfeffer K Biochem J. 2024 Aug 6:BCJ20240110. doi: 10.1042/BCJ20240110. PMID:39105673^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.