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Chlorflavonin Targets Acetohydroxyacid Synthase Catalytic Subunit IlvB1 for Synergistic Killing of Mycobacterium tuberculosis

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† Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225 Düsseldorf, Germany
∥ Faculty of Science, Department of Chemistry, University of Douala, PO Box 24157, 2701 Douala, Cameroon
‡ Department of Computer Science, Texas A&M University, 710 Ross St., College Station, Texas 77843, United States
§ Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225 Düsseldorf, Germany
*Phone: +49 211 8114180. E-mail: [email protected] (R.K.).
*Phone: +49 211 8114163. E-mail: [email protected] (P.P.).
Cite this: ACS Infect. Dis. 2018, 4, 2, 123–134
Publication Date (Web):November 6, 2017
https://doi.org/10.1021/acsinfecdis.7b00055
Copyright © 2017 American Chemical Society
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    Abstract

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    The flavonoid natural compound chlorflavonin was isolated from the endophytic fungus Mucor irregularis, which was obtained from the Cameroonian medicinal plant Moringa stenopetala. Chlorflavonin exhibited strong growth inhibitory activity in vitro against Mycobacterium tuberculosis (MIC90 1.56 μM) while exhibiting no cytotoxicity toward the human cell lines MRC-5 and THP-1 up to concentrations of 100 μM. Mapping of resistance-mediating mutations employing whole-genome sequencing, chemical supplementation assays, and molecular docking studies as well as enzymatic characterization revealed that chlorflavonin specifically inhibits the acetohydroxyacid synthase catalytic subunit IlvB1, causing combined auxotrophies to branched-chain amino acids and to pantothenic acid. While exhibiting a bacteriostatic effect in monotreatment, chlorflavonin displayed synergistic effects with the first-line antibiotic isoniazid and particularly with delamanid, leading to a complete sterilization in liquid culture in combination treatment. Using a fluorescent reporter strain, intracellular activity of chlorflavonin against Mycobacterium tuberculosis inside infected macrophages was demonstrated and was superior to streptomycin treatment.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsinfecdis.7b00055.

    • Analytical data for chlorflavonin (3) including 1H (Figure S1), 13C (Figure S2), HSQC (Figure S3), HMBC (Figure S4), and ROESY (Figure S5) NMR spectra and key 2D NMR correlations of 3 (Figure S6); comparative dose–response curves for chlorflavonin (3), dechlorochlorflavonin (2), and terphenyllin (1) (Figure S7); docking solutions of sulfometuron methyl and chlorflavonin (Figure S8); NMR spectroscopic data of 3 (Table S1); checkerboard synergy assay (Table S2) (PDF)

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