Activity of (-)-Camphene Derivatives Against Mycobacterium tuberculosis in Acidic pH

Abstract

Background: For more than 60 years, the lack of new anti-tuberculosis drugs and the increase of resistant Mycobacterium tuberculosis lineages exhibit a therapeutic challenge, demanding new options for the treatment of resistant tuberculosis. Objective: Herein, we determined the (i) activities of (-)-camphene and derivatives and (ii) combinatory effect with pyrazinamide (PZA) against Mycobacterium tuberculosis in acidic pH and (iii) cytotoxicity in VERO cells. Methods: The activity of (-)-camphene and 15 derivatives were determined in M. tuberculosis H37Rv in culture medium at pH 6.0 by Resazurin Microtiter Assay Plate (REMA). The combinatory study of three (-)-camphene derivatives with PZA was carried out in seven multidrug-resistant (MDR) clinical isolates by REMA and Checkerboard, respectively. The assay of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) bromide in VERO cells was used to determine the derivatives cytotoxicity. Results: Four (-)-Camphene derivatives, (4), (5a) (5d) and (5h), showed reduction in MIC value at pH 6.0 compared to MIC detected at pH 6.8 in M. tuberculosis H37Rv and multidrug resistant clinical isolates. Three (-)-camphene derivatives, (4), (5d) and (5h), showed synergistic effect (FICI ≤ 0.5) combined with PZA and were more selective for M. tuberculosis than VERO cell (selective index from 7.7 to 84.2). Conclusion: Three (-)-camphene derivatives have shown to be promising anti-TB molecule scaffold due to the low MIC values in acidic pH against MDR M. tuberculosis clinical isolates, synergism with PZA and low cytotoxicity.

Immunomodulatory Activity of Diterpenes over Innate Immunity and Cytokine Production in a Human Alveolar Epithelial Cell Line Infected with Mycobacterium tuberculosis

“…Several studies have demonstrated the antimycobacterial, immunomodulatory and adjuvant activities of terpenoids [ 33 ]. For instance, the monoterpene camphene and its derivatives exhibited low MIC values against M. tb clinical isolates, synergism with the antitubercular-drug pyrazinamide and low cytotoxicity [ 34 ]. The terpenes commiphoroid E and F, at 200 μM concentration, inhibited the growth of both sensitive and clinically multi-drug resistant (MDR) M. tb isolated strains.…”

Success stories of natural product-derived compounds from plants as multidrug resistance modulators in microorganisms

“…The (−)-camphene derivatives tested in the present study, particularly (4) (5d) and (5 h), were shown to be promising anti-TB molecule scaffolds due to the low MIC values in acidic pH against the reference strain H37Rv and MDR M. tuberculosis clinical isolates, their low cytotoxicity and the synergism observed with PZA. 137 All bacteria tested were inhibited by the highest polar fraction of Cistus ladaniferus essential oil, which contained monoand sesquiterpene alcohols with MIC values ranging from 0.05 to 0.8 mg mL −1 . 138 There was high activity of this fraction against the MDR strsain Enterobacter aerogenes EA289, and its mechanism involves a distortion of the cell wall with detachment of the outer cytoplasmic membrane.…”

“…The (−)-camphene derivatives tested in the present study, particularly (4) (5d) and (5 h), were shown to be promising anti-TB molecule scaffolds due to the low MIC values in acidic pH against the reference strain H37Rv and MDR M. tuberculosis clinical isolates, their low cytotoxicity and the synergism observed with PZA. 137…”

Camphene as a Protective Agent in Myocardial Ischemia/Reperfusion Injury

“…Camphene is used as an additive in foods and fragrances, and it is included in essential oils as well [15]. It has been recognized to have antibiotic anti-fungal [16][17][18], anti-inflammatory, and analgesic properties [19,20], while it is also used as an expectorant [21] and antinociceptive [22]. Furthermore, camphene has been reported to exhibit a hypolipidemic action [23] while it increases the expression of apolipoprotein ApoA1 protein levels in a dose-dependent manner [24], resulting in increased formation of high-density lipoprotein (HDL) molecules [23].…”