Effluxosomes and the evolution of metal resistance in <i>Mycobacterium tuberculosis</i>

ABSTRACT During infection, host immune cells deploy a variety of strategies to neutralize invading pathogens, including the manipulation of metal availability, a process traditionally understood as nutritional immunity. While depriving microbes of essential metals, such as iron and manganese, inhibits their growth, host cells also engage in metal intoxication, actively overloading phagosomes with toxic levels of transition metals, such as copper and zinc. To survive these dual pressures, Mycobacterium tuberculosis , the etiological agent of tuberculosis, has evolved specialized metal resistance mechanisms. This review explores how M. tuberculosis counters host-imposed metal stress through an arsenal of P-type ATPases, particularly the diverse P 1B subfamily of transition metal exporters. We detail the structural features, metal specificities, and regulatory mechanisms of M. tuberculosis ’ 12 P-type ATPases, focusing on three key systems, CtpC, CtpG, and CtpV, and their cognate scaffold proteins PacL1, PacL2, and PacL3. These PacL-Ctp pairs form dynamic membrane assemblies termed effluxosomes, which mediate resistance to transition metals such as zinc and cadmium. The review also highlights several distinctive features of M. tuberculosis P 1B -ATPases relative to canonical transporters such as CopA and ZntA, suggesting unique adaptations to the intracellular environment. Finally, we discuss the challenges of functionally and structurally characterizing these systems and propose future directions to elucidate effluxosome assembly and function. Together, these insights reveal how M. tuberculosis leverages metal export as a critical survival strategy and suggest novel therapeutic opportunities targeting metal detoxification pathways.