Hydrogen sulfide stimulates Mycobacterium tuberculosis respiration, growth and pathogenesis.

Hydrogen sulfide (HS) is involved in numerous pathophysiological processes and shares overlapping functions with CO and •NO. However, the importance of host-derived HS in microbial pathogenesis is unknown. Here we show that Mtb-infected mice deficient in the HS-producing enzyme cystathionine β-synthase (CBS) survive longer with reduced organ burden, and that pharmacological inhibition of CBS reduces Mtb bacillary load in mice. High-resolution respirometry, transcriptomics and mass spectrometry establish that HS stimulates Mtb respiration and bioenergetics predominantly via cytochrome bd oxidase, and that HS reverses •NO-mediated inhibition of Mtb respiration. Further, exposure of Mtb to HS regulates genes involved in sulfur and copper metabolism and the Dos regulon. Our results indicate that Mtb exploits host-derived HS to promote growth and disease, and suggest that host-directed therapies targeting HS production may be potentially useful for the management of tuberculosis and other microbial infections.