Effect of Linezolid plus Bedaquiline against Mycobacterium tuberculosis in Log-Phase, Acid-Phase and Non-Replicating-Persister (NRP)-Phase in an In vitro Assay [PublishAheadOfPrint]

Tuberculosis is the ninth-leading cause of death worldwide. Treatment success is approximately 80% for susceptible strains and decreases to 30% for extensively resistant strains. Shortening therapy duration for Mycobacterium tuberculosis (Mtb) is a major goal, which can be attained with the use of combination therapy. However, the identification of the most promising combination is a challenge given the quantity of older and newer agents available. Our objective was to identify promising 2-drug combinations using an in vitro strategy to ultimately be tested in an in vitro Hollow Fiber Infection Model (HFIM) and in animal models. We studied the effect of the combination of linezolid (LZD) and bedaquiline (BDQ) on Mtb strain H37Rv in Log- and Acid-Phase growth and Mtb strain 18b in Log- and Non-Replicating-Persister-Phase growth in a plate system containing a 9 x 8 matrix of concentrations of both drugs alone and in combinations. Characterization of the interaction as antagonistic, additive, or synergistic was performed using the Greco Universal Response Surface Approach (URSA) model. Our results indicate that the interaction between LZD and BDQ is additive for bacterial killing in both strains for both of the metabolic states tested. This prescreen strategy was suitable to identify LZD and BDQ as a promising combination to be further tested in the HFIM. The presence of non-overlapping mechanisms of drug action suggests each drug in the combination will likely be effective in suppressing emergence of resistance by Mtb to the companion drug, which holds promise in improving treatment outcomes for tuberculosis.

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