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Open AccessFeature PaperArticle

Flavonoids as Novel Efflux Pump Inhibitors and Antimicrobials Against Both Environmental and Pathogenic Intracellular Mycobacterial Species

1
Institute of Pharmaceutical Sciences, Department of Pharmacognosy, University of Graz, 8010 Graz, Austria
2
Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, London WC1E 7HX, UK
*
Author to whom correspondence should be addressed.
Molecules 2020, 25(3), 734; https://doi.org/10.3390/molecules25030734
Received: 20 December 2019 / Revised: 31 January 2020 / Accepted: 6 February 2020 / Published: 7 February 2020
Therapeutic treatment options for opportunistic non-tuberculous mycobacterial (NTM) infection and/or serious mycobacterial infections such as tuberculosis (TB) and leprosy are limited due to the spread of antimicrobial resistance mechanism. Plant-derived natural compounds as prospective efflux pump inhibitors may present a promising adjunct to conventional chemotherapy by enhancing mycobacterial susceptibility to antibiotics. This study served to evaluate the antimicrobial and resistance-modifying profile of a range of plant-derived flavonoids against the mycobacterial model strains: M. smegmatis, M. aurum, and M. bovis BCG. The minimum inhibitory concentrations (MICs) of the compounds against the mycobacterial strains were determined using both agar dilution and broth dilution assays, while their efflux inhibitory activity was investigated via an ethidium bromide-based fluorometric assay. All compounds were screened for their synergistic effects with ethidium bromide (EtBr) and rifampicin (RIF) against M. smegmatis. Skullcapflavone II (5,2′-dihydroxy-6,7,8,6′-tetramethoxyflavone, 1) exerted potent antimicrobial activity against M. aurum and M. bovis BCG and considerably increased the susceptibility of M. smegmatis to EtBr and RIF. Nobiletin (5,6,7,8,3′,4′-hexamethoxyflavone, 2) was determined to be the most potent efflux-inhibitor in M. aurum and M. smegmatis. However, a connection between strong modulatory and putative efflux activity of the compounds could not be observed. Nevertheless, the results highlight two polymethoxyflavones, skullcapflavone II and nobiletin, with potent antimycobacterial and antibiotic resistance modulating activities as valuable adjuvants in anti-mycobacterial therapies. View Full-Text
Keywords: flavonoids; skullcapflavone II; nobiletin; efflux pumps; efflux pump inhibitors; mycobacteria flavonoids; skullcapflavone II; nobiletin; efflux pumps; efflux pump inhibitors; mycobacteria
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Solnier, J.; Martin, L.; Bhakta, S.; Bucar, F. Flavonoids as Novel Efflux Pump Inhibitors and Antimicrobials Against Both Environmental and Pathogenic Intracellular Mycobacterial Species. Molecules 2020, 25, 734.

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