Assessing the efficacy of combined treatment using bedaquiline against clinical isolates of multidrug-resistant Mycobacterium tuberculosis in vitro and the macrophage model

Combination treatments can shorten treatment time and reduce drug side effects. The aim of this study was to assess the efficacy of combined treatment using bedaquiline (BDQ) against clinical isolates of multidrug-resistant (MDR) Mycobacterium tuberculosis (M. tuberculosis). This cross-sectional study was performed on 15 drug-resistant isolates of M. tuberculosis. After determining the Minimum inhibitory concentration (MIC) of antibiotics, the fractional inhibitor concentration index (FICI) was evaluated using a checkerboard resazurin microtitration assay (REMA) to evaluate their interaction profiles against the M. tuberculosis isolates. The macrophage model was used to study the activity of synergistic compounds and the expression level of macrophage genes were evaluated by real-time PCR. All isolates had MIC ≥ 0.25 µg/mL for BDQ. Of the 15 isolates, only 2 observed a synergistic effect between BDQ and other antibiotics. The expression of macrophage genes (FABP5, HERG, RPL24, and SCARB1) infected with these two isolates, was significantly increased by the combination of BDQ+ gemifloxacin (GEM), BDQ + Rifampicin (RIF), BDQ + moxifloxacin (MFX), and BDQ + isoniazid (INH) (p < 0.01). Despite resistance to BDQ, the combination treatments showed a positive effect in the macrophage cell line model. Therefore, it can be concluded that the combination treatment with BDQ may enhanced the innate immune response of macrophages against M. tuberculosis infection and also reduce the MIC of BDQ and other antibiotics in combination with it. This suggests a potential for more effective treatment for drug-resistant isolates.