Iron–sulfur proteins in mycobacteria: master regulators of physiology and pathogenesis

Abstract

Iron–sulfur ([Fe-S]) cluster proteins are essential cofactors that support key biological processes in bacteria. Among the various [Fe–S] protein biogenesis systems (ISC, SUF, NIF, MIS, SMS), mycobacterial species rely exclusively on the sulfur utilization factor (SUF) machinery for [Fe–S] cluster biogenesis. In this review, we summarize current knowledge of the SUF system in bacteria and compare it with other [Fe–S] protein biogenesis systems. We outline the cellular sources of iron and sulfur in mycobacteria, propose a global model for [Fe–S] cluster assembly, and present an overview of [Fe–S] proteins in Mycobacterium tuberculosis and other mycobacterial species, emphasizing their roles in virulence, persistence, metabolism, and antibiotic resistance. Finally, we discuss emerging inhibitors targeting [Fe–S]-dependent pathways and their potential as antimycobacterial agents. Together, this overview provides a framework for unraveling the complexity of [Fe–S]-based metabolism in mycobacteria and highlights new opportunities for therapeutic intervention.