Mycobacterial respiratory chain enzymes and growth are inhibited by decylubiquinone

Aerobic organisms obtain energy by linking electron transfer from NADH to O₂, through the respiratory chain, to transmembrane proton translocation. In mycobacteria the respiratory chain is branched; the membrane-bound electron carrier menaquinol (MQH₂) donates electrons either to the O₂-reducing cytochrome bd or a supercomplex that is composed of a complex (C) III₂ dimer flanked by two CIVs. Here, we measured the dimethyl-naphthoquinone (DMNQH_2, a menaquinol analogue) oxidation:O₂ reduction activities of the CIII₂CIV₂ supercomplex and cytochrome bd in the presence of an analogue (decylubiquinone, DCQ) of the mammalian electron carrier, ubiquinol. The data show that DCQH₂ inhibits both the CIII₂CIV₂ and cytochrome bd activities, suggesting that DCQ/DCQH₂ interferes with both branches of the respiratory chain. Cryo-EM data of the M. smegmatis supercomplex shows that oxidized DCQ binds in the electron donor site (Q_o) of CIII₂. Accordingly, growth of M. smegmatis cells was impaired in the presence of DCQ. Remarkably, DCQ also impairs intracellular growth of virulent M. tuberculosis cells in human primary macrophages suggesting that the compound could potentially be used as an adjuvant during tuberculosis disease treatment.