Figure 7.

Proposed mechanism of action for the nitronaphthofuran nNF-C2. The nNF-C2 is reduced by Mrx2 which uses mycothiol (MSH) as cofactor. The reduction of the nNF-C2 nitro group leads to the release of nitric oxide (NO) and yet unknown secondary metabolites, which target the viability of M. tuberculosis and also promote the activation of a stress response in M. tuberculosis. In this programmed stress response, the expression of the alternative sigma factor SigH and its antisigma factor RshA - which is co-transcribed with SigH - are induced. Oxidative stress causes the release of the antisigma factor RshA from SigH, thus enabling SigH to exert its action as a transcriptional factor inducing the sigH regulon, in which mrx2 is included. Higher expression levels of mrx2 increase the ratio of nNF-C2 activation, that in turn enhances the production of NO and reactive metabolites, which keep inducing the sigH expression. We propose that the reduction of nNF-C2 is enhanced by elevated levels of intracellular mycothiol, SigH, and Mrx2 under oxidizing conditions (highlighted in blue). This positive feedback loop would explain the killing activity of nNF-C2 on replicating, non-replicating, and intracellular M. tuberculosis.