Nitrate-nitrite fate and oxygen sensing in dormant Mycobacterium tuberculosis A bioinorganic approach highlighting the importance of transition metals

Mycobacterium tuberculosis (Mtb), the agent of tuberculosis (TB), is able to adapt to unfavorable environments within the human host. The World Health Organization (WHO) reported that 1/4 of the world population is infected by dormant Mtb. This state of dormancy corresponds to a non-replicating persistent form with decreased sensitivity to most drugs. During dormancy within a granuloma, there is limited access to nutrients, including oxygen (O₂), and sources of nitrogen. Consequently, hypoxia adaptation and nitrate/nitrite metabolism play crucial roles in the dormancy process that are better understood in a connected context. This review discusses a series of systems involved in nitrogen metabolism in bacteria and, particularly, in Mtb, along with the essential role of O₂ and nitrite sensors involved in dormancy. The assemble of the enzymes/proteins involved in these processes, thoroughly discussed in the text, covers nitrate and nitrite reductases (Mo, Cu, heme Fe and Fe/S containing enzymes), along with kinases (histidine and serine/threonine, Mn/Mg-dependent) and sensors (heme Fe and Fe/S containing), where we present their interconnected roles. The complex O₂ sensing system, described as DevS (DosS) and DosT, uses heme-based sensors and is also reviewed. Interestingly, the large majority of these proteins bring metals such as Fe, Mo, Cu, Mg, Mn to the discussion of their crucial roles and to the understanding of Mtb metabolism, and arise exciting challenges to bioinorganic chemistry. Moreover, some of these proteins have been pursued as potential drug targets, opening further opportunities for therapy. Overall, this review frames what is currently known about oxygen and nitrogen metabolisms and sensing in dormant Mtb, opening avenues for possible strategies for tuberculosis treatment.