A bioinorganic chemistry perspective on the roles of metals as drugs and targets against Mycobacterium tuberculosis - a journey of opportunities

Medicinal inorganic chemists have provided many strategies to tackle a myriad of diseases, pushing forward the frontiers of pharmacology. As an example, the fight against tuberculosis (TB), an infectious bacterial disease, has led to the development of metal-based compounds as potential drugs. This disease remains a current health issue causing over 1.4 million of deaths per year. The emergence of multi- (MDR) and extensively-drug resistant (XDR) Mycobacterium tuberculosis (Mtb) strains along with a long dormancy process, place major challenges in developing new therapeutic compounds. Isoniazid is a front-line prodrug used against TB with appealing features for coordination chemists, which have been explored in a series of cases reported here. An isoniazid iron-based compound, called IQG-607, has caught our attention, whose in vitro and in vivo studies are advanced and thoroughly discussed, along with other metal complexes. Isoniazid is inactive against dormant Mtb, a hard to eliminate state of this bacillus, found in one-fourth of the world's population and directly implicated in the lengthy treatment of TB (ca. 6 months). Thus, our understanding of this phenomenon may lead to a rational design of new drugs. Along these lines, we describe how metals as targets can cross paths with metals used as selective therapeutics, where we mainly review heme-based sensors, DevS and DosT, as a key system in the Mtb dormancy process and a current drug target. Overall, we report new opportunities for bioinorganic chemists to tackle this longstanding and current threat.