Fig. 4: Altered killing dynamics of drug-resistant variants of M. tuberculosis following exposure to collateral antibiotics.

a–d Minimum bactericidal concentration assays for selected drug-resistant variants and the drug-susceptible parent against selected antibiotics. CFUs were determined at day 0 and at day 10 for concentrations at and above the minimum inhibitory concentrations (i.e. 1, 3, 9, and 27× MIC of the drug-susceptible parent) of selected compounds. Inoc = starting inoculum on day 0, DMSO = solvent control. e–h Time kill experiments of selected drug-resistant variants and the drug-susceptible parent against selected antibiotics at concentrations above the minimum inhibitory concentration (9x MIC). CFUs were taken at stated time points. i Frequency of resistance for selected drug-resistant mutants and drug-susceptible parental strain against 9× PA824. Statistical significance was investigated using a one-way ANOVA and corrected for multiple comparisons using the Dunnett’s multiple comparisons test (95% CI). ns = not significant. j–l Co-culture time kills. Drug-susceptible parent strain and INH-1 were combined at 1:1 ratio and challenged with BDQ, TAC or PA824 above minimum inhibitory concentrations (9× MIC). CFUs were taken at stated time points and plated on 7H11 with/without 9× MIC INH to determine the proportion of INH-1 in the co-culture relative to the drug-susceptible parent. For a–h, data are the mean ± range of biological duplicates from a representative experiment (n > 2 independent experiments). For i, data are the mean of eight biological replicates. For j–l, data are the mean ± range of biological duplicates from a representative experiment (n > 2 independent experiments). Strain names and resistance mutations are listed. Dashed lines represent upper and lower limits of detection. DMSO solvent control graphs are included in Supplementary Fig. 5.