Kendomycin Cytotoxicity against Bacterial, Fungal, and Mammalian Cells Is Due to Cation Chelation.

Dale Tranter,Ireos Filipuzzi,Juho Kellosalo,Axel Meissner,Dominic Hoepfner,Thomas Lochmann,David Estoppey,Britta Knapp,Ville O Paavilainen,Dominik Pistorius

doi:10.1021/acs.jnatprod.9b00826

Dale Tranter, Ireos Filipuzzi + Show 8 more

Open Access

https://doi.org/10.1021/acs.jnatprod.9b00826

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Abstract

Kendomycin is a small-molecule natural product that has gained significant attention due to reported cytotoxicity against pathogenic bacteria and fungi as well as a number of cancer cell lines. Despite significant biomedical interest and attempts to reveal its mechanism of action, the cellular target of kendomycin remains disputed. Herein it is shown that kendomycin induces cellular responses indicative of cation stress comparable to the effects of established iron chelators. Furthermore, addition of excess iron and copper attenuated kendomycin cytotoxicity in bacteria, yeast, and mammalian cells. Finally, NMR analysis demonstrated a direct interaction with cations, corroborating a close link between the observed kendomycin polypharmacology across different species and modulation of iron and/or copper levels.

Highlights

Kendomycin is a small-molecule natural product that has gained significant attention due to reported cytotoxicity against pathogenic bacteria and fungi as well as a number of cancer cell lines
To test whether proteasome inhibition plays a role in kendomycin cytotoxicity in human cells, a FACS-based proteasomal degradation assay was used that monitors cellular turnover of a destabilized UbG76V-GFP reporter as a measure of proteasome activity.[6]
Kendomycin has been shown to affect the uptake of radiolabeled isoleucine in bacteria, indicative of protein synthesis inhibition.[7]

Summary

Introduction

Kendomycin is a small-molecule natural product that has gained significant attention due to reported cytotoxicity against pathogenic bacteria and fungi as well as a number of cancer cell lines. Fluorescence even at acutely cytotoxic concentrations (Figures 1B and S1, Supporting Information), suggesting direct proteasome inhibition is not likely the primary mechanism of action of kendomycin.[2]

Results

Conclusion