Host Bioenergetic Parameters Reveal Cytotoxicity of Antituberculosis Drugs Undetected Using Conventional Viability Assays
| Autor: | Kelvin W. Addicott, Dongquan Chen, Zainab Baig, Adrie J. C. Steyn, Bridgette M. Cumming |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Drug Cell type medicine.medical_treatment media_common.quotation_subject Antitubercular Agents Pharmacology Mycobacterium tuberculosis 03 medical and health sciences 0302 clinical medicine medicine Humans Tuberculosis Pharmacology (medical) Viability assay Cytotoxicity Mode of action media_common biology Chemistry Macrophages biology.organism_classification 030104 developmental biology Infectious Diseases Cytokine Drug development Erratum Energy Metabolism 030217 neurology & neurosurgery |
| Zdroj: | Antimicrob Agents Chemother |
| ISSN: | 1098-6596 |
| Popis: | High attrition rates in tuberculosis (TB) drug development have been largely attributed to safety, which is likely due to the use of endpoint assays measuring cell viability to detect drug cytotoxicity. In drug development for cancer, metabolic, and neurological disorders and for antibiotics, cytotoxicity is increasingly being assessed using extracellular flux (XF) analysis, which measures cellular bioenergetic metabolism in real time. Here, we adopt the XF platform to investigate the cytotoxicity of drugs currently used in TB treatment on the bioenergetic metabolism of HepG2 cells, THP-1 macrophages, and human monocyte-derived macrophages (hMDMs). We found that the XF analysis reveals earlier drug-induced effects on the cells' bioenergetic metabolism prior to cell death, measured by conventional viability assays. Furthermore, each cell type has a distinct response to drug treatment, suggesting that more than one cell type should be considered to examine cytotoxicity in TB drug development. Interestingly, chemically unrelated drugs with different modes of action on Mycobacterium tuberculosis have similar effects on the bioenergetic parameters of the cells, thus discouraging the prediction of potential cytotoxicity based on chemical structure and mode of action of new chemical entities. The clustering of the drug-induced effects on the hMDM bioenergetic parameters are reflected in the clustering of the effects of the drugs on cytokine production in hMDMs, demonstrating concurrence between the effects of the drugs on the metabolism and functioning of the macrophages. These findings can be used as a benchmark to establish XF analysis as a new tool to assay cytotoxicity in TB drug development. |
| Databáze: | OpenAIRE |
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