Combinations of Respiratory Chain Inhibitors Have Enhanced Bactericidal Activity against Mycobacterium tuberculosis

As an obligate aerobe, Mycobacterium tuberculosis uses its electron transport chain (ETC) to produce energy via oxidative phosphorylation. This pathway has recently garnered a lot of attention and is a target for several new antimycobacterials. We tested the respiratory adaptation of M. tuberculosis to phenoxyalkylbenzimidazoles (PABs), compounds proposed to target QcrB, a component of the cytochrome bc₁ complex. We show that M. tuberculosis is able to reroute its ETC to provide temporary resistance to PABs. However, combination treatment of PAB with agents targeting other components of the electron transport chain overcomes this respiratory flexibility. PAB in combination with clofazimine resulted in synergistic killing of M. tuberculosis under both replicating and nonreplicating conditions. PABs in combination with bedaquiline demonstrated antagonism at early time points, particularly under nonreplicating conditions. However, this antagonistic effect disappeared within 3 weeks, when PAB-BDQ combinations became highly bactericidal; in some cases, they were better than either drug alone. This study highlights the potential for combination treatment targeting the ETC and supports the development of PABs as part of a novel drug regimen against M. tuberculosis.