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Molecules 2018, 23(1), 176;

The Effect of Combining Natural Terpenes and Antituberculous Agents against Reference and Clinical Mycobacterium tuberculosis Strains

Department of Pharmacognosy with Medicinal Plant Unit, Medical University of Lublin, 20-093 Lublin, Poland
Department of Biochemistry and Biotechnology, Medical University of Lublin, 20-093 Lublin, Poland
Department of Microbiology, National Tuberculosis and Lung Diseases Research Institute, 01-138 Warsaw, Poland
Author to whom correspondence should be addressed.
Received: 28 November 2017 / Revised: 28 December 2017 / Accepted: 6 January 2018 / Published: 15 January 2018
(This article belongs to the Special Issue Essential Oils as Antimicrobial and Anti-infectious Agents)
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Background: On account of emergence of multi- and extensively drug-resistant Mycobacterium tuberculosis (Mtb) strains, combinations of drugs with natural compounds were tested to search for antibiotic activity enhancers. In this work we studied terpenes (α-pinene, bisabolol, β-elemene, (R)-limonene, (S)-limonene, myrcene, sabinene), which are the main constituents of essential oil obtained from Mutellina purpurea L., a plant with described antitubercular activity, to investigate their interactions with antibiotics against reference Mtb strains and multidrug-resistant clinical isolates. Methods: The serial dilution method was used to evaluate the minimal inhibitory concentration (MIC) of tested compounds, while the fractional inhibitory concentration index (FICI) was calculated for characterization of interactions. Moreover, IC50 values of tested compounds were determined using monkey kidney epithelial cell line (GMK). Results: The combinations of all studied terpenes with ethambutol or rifampicin resulted in a synergistic interaction. Bisabolol and (R)-limonene decreased the MIC for rifampicin at least two-fold for all tested strains, however no synergistic action was observed against virulent strains. The tested terpenes showed slight (bisabolol) or no cytotoxic effect against normal eukaryotic cells in vitro. Conclusions: The obtained enhanced activity (FICI < 0.5) of ethambutol and rifampicin against H37Ra strain under the influence of the studied terpenes may be correlated to the capability of essential oil constituents to modify bacterial resistance mechanisms in general. The observed differences in avirulent and virulent bacteria susceptibility to terpenes tested separately and in combinations with antibiotics can be correlated with the differences in the cell wall structure between H37Ra mutant and all virulent strains. View Full-Text
Keywords: FICI; MDR-TB; clinical isolates; natural terpenes; bisabolol; (R)-limonene FICI; MDR-TB; clinical isolates; natural terpenes; bisabolol; (R)-limonene
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Sieniawska, E.; Sawicki, R.; Swatko-Ossor, M.; Napiorkowska, A.; Przekora, A.; Ginalska, G.; Swatko-Ossor, M.; Augustynowicz-Kopec, E. The Effect of Combining Natural Terpenes and Antituberculous Agents against Reference and Clinical Mycobacterium tuberculosis Strains. Molecules 2018, 23, 176.

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