The Essential Transition Metals Transport Systems in Mycobacterium tuberculosis: A Scoping Review of Emerging Targets for Antitubercular Drug Discovery

In 2023, tuberculosis (TB) once again became the leading cause of death from a single infectious agent, with 1.25 million fatalities. Current TB treatment relies on the combination of drugs with different targets of action, as monotherapies have proven less effective and promoted the rapid emergence of resistance. Transition metals play an essential role in the metabolism of Mycobacterium tuberculosis (Mtb), influencing its growth and virulence. Restriction or exposure to toxic concentrations of these metals represent host cell defense mechanisms against Mtb. This scoping review aimed to map the main protein targets involved in the transport of essential transition metals across the Mtb membrane and to assess their potential in the development of novel anti-tuberculosis agents. The review was conducted according to JBI Collaboration guidelines and reported following the PRISMA-ScR checklist. Searches were carried out in PubMed, Web of Science, and Embase for studies published up to March 2025. A total of 72 studies were included, with iron being the most investigated metal (n = 48). The mechanisms of iron influx and efflux in Mtb are relatively well characterized; however, significant knowledge gaps persist regarding the role of the ESX-3 secretion system and the translocation of siderophores across the outer membrane. For each of the 79 entries mapped, database annotation was recorded separately from the evidence demonstrated in the included studies; in 65 entries the annotated direction of transport was not demonstrated experimentally. Comparing candidates by the level of functional evidence obtained in M. tuberculosis, the evidence available from macrophage and animal infection models and the existence of alternative pathways indicate that ESX-3, IrtAB and the siderophore export platform are the most completely supported systems; no inhibitor of any of these systems is reported in the included studies.