Antitrypanosomal 8-Hydroxy-Naphthyridines Are Chelators of Divalent Transition Metals.

Antimicrobial Agents and Chemotherapy
Richard J WallSusan Wyllie

Abstract

The lack of information regarding the mechanisms of action (MoA) or specific molecular targets of phenotypically active compounds can prove a barrier to their development as chemotherapeutic agents. Here, we report the results of our orthogonal genetic, molecular, and biochemical studies to determine the MoA of a novel 7-substituted 8-hydroxy-1,6-naphthyridine (8-HNT) series that displays promising activity against Trypanosoma brucei and Leishmania donovani High-throughput loss-of-function genetic screens in T. brucei highlighted two probable zinc transporters associated with resistance to these compounds. These transporters localized to the parasite Golgi apparatus. Directed by these findings, the role of zinc and other divalent cations in the MoA of these compounds was investigated. 8-HNT compounds were found to directly deplete intracellular levels of Zn2+, while the addition of exogenous Zn2+ and Fe2+ reduced the potency of compounds from this series. Detailed biochemical analyses confirmed that 8-HNT compounds bind directly to a number of divalent cations, predominantly Zn2+, Fe2+, and Cu2+, forming 2:1 complexes with one of these cations. Collectively, our studies demonstrate transition metal depletion, due to chelation, ...Continue Reading

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Citations

Dec 18, 2018·Frontiers in Microbiology·Sanjay VarikutiAbhay R Satoskar
Oct 30, 2021·Journal of Medicinal Chemistry·Charles E MowbraySusan Wyllie

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Datasets Mentioned

BETA
PRJEB21480

Methods Mentioned

BETA
RIT-seq
PCR
transfection

Software Mentioned

Protter
SAMtools
Artemis genome browser
QuanOptimize
Bowtie
Erithacus
ClustalX
GRAFIT

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