All organisms require iron-sulfur (Fe-S) clusters to carry out essential cellular processes, such as respiration and gene expression. Fe-S clusters are assembled in four known pathways, called the SUF, ISC, NIF, and CIA pathways. In general, these pathways function by (1) abstracting sulfur from a free cysteine substrate using a cysteine desulfurase, (2) assembling an Fe-S cluster in a scaffold protein or protein complex, and then (3) transferring the cluster to a target apo-protein. Most organisms express redundant pathways. However, some Gram-positive bacteria, such as Bacillus subtilis and Staphylococcus aureus, exclusively express and rely on the SUF-like pathway for Fe-S cluster biosynthesis. In these organisms, the component proteins of the SUF-like pathway are essential. In pathogenic bacteria, such as S. aureus, these proteins are therefore potential candidates for drug discovery toward the development of new antibacterial agents. In this presentation, I will summarize my lab’s efforts to characterize and inhibit proteins from the SUF-like pathway in S. aureus. Our work confirms the structure, function, and activity of the cysteine desulfurase (SufS) and sulfur-shuttling (SufU) proteins from S. aureus in comparison to SufS and SufU from B. subtilis, which is a well-studied, non-pathogenic model organism for the SUF-like pathway. I will also discuss our evaluation of the potential druggability of SufS and SufU in S. aureus.

Characterization and inhibition of the SUF-like pathway of Fe-S cluster biosynthesis in Staphylococcus aureus

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ACS Fall 2022

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