# Mycobacterial respiratory chain enzymes and growth are inhibited by decylubiquinone

## TL;DR

This study shows that decylubiquinone inhibits key respiratory enzymes in mycobacteria and slows their growth, including that of tuberculosis-causing bacteria.

## Contribution

Decylubiquinone is shown to inhibit both branches of the mycobacterial respiratory chain and impair M. tuberculosis growth in macrophages.

## Key findings

- Decylubiquinone inhibits the CIII2CIV2 supercomplex and cytochrome bd in mycobacteria.
- Decylubiquinone impairs the growth of M. smegmatis and M. tuberculosis in human macrophages.
- Cryo-EM reveals decylubiquinone binds at the Qo site of the CIII2 complex.

## Abstract

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 (DMNQH2, 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 (Qo) 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.

Using a combination of cryo-electron microscopy, activity measurements and in vivo experiments, the authors show that decylubiquinone, an analogue of the mammalian electron carrier, ubiquinol, binds to and inhibits the CIII2CIV2 supercomplex from M. smegmatis, and inhibits growth of M. tuberculosis. This compound may thus represent a new therapeutic strategy to treat tuberculosis.