Some of the differentially expressed proteins have the potential to be drug targets such as citrate synthase (Rv0896), phosphoglycerate kinase (Rv1437), ketol-acid reductoisomerase (Rv3001c) and ATP synthase alpha chain (Rv1308).

Considering the functions of these proteins our results support that the intermediary metabolism and respiration were affected by EMB and this disturbance provided proteins that could be explored as additional targets for this drug.

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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.

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