PhD Defense
Olivia Stiller
Monday, April 7th, 2025 at 1 PM (CST)
Sugihara 252

BIOPHYSICAL INVESTIGATION OF REGULATORY INTERACTIONS BETWEEN ENZYMES FROM THE HEME BIOSYNTHESIS AND HEME ACQUISITION PATHWAYS IN STAPHYLOCOCCUS AUREUS
The World Health Organization predicts that by 2050, drug-resistant infections will become the leading cause of death worldwide. Addressing the rising threat posed by these “superbugs” necessitates the development of innovative antibiotic strategies. This thesis contributes by identifying and understanding the biochemical vulnerabilities of these pathogens. Iron is essential for the growth and virulence of nearly all pathogenic bacteria, including the Gram-positive pathogen Staphylococcus aureus. Three known pathways exist for heme b biosynthesis: the siroheme-dependent pathway in archaea and certain bacteria, the protoporphyrin-dependent pathway in Gram-negative bacteria and eukaryotes, and the coproporphyrin-dependent (CPD) pathway recently identified in Gram-positive bacteria. Since heme is cytotoxic, its production and import must be tightly regulated, making these processes critical for bacterial survival. This thesis aims to explore the interactions between iron acquisition and heme biosynthesis pathways in S. aureus to better understand heme homeostasis. A deeper insight into this interplay can inform the design of drugs targeting one or both pathways. The research focuses on three key areas: 1) Investigating the catalytic mechanism of coproheme decarboxylase. 2) Characterizing interactions between the final two enzymes of the CPD pathway and 3)Examining the interactions of coproporphyrin ferrochelatase and coproheme decarboxylase with heme oxygenases IsdI and IsdG, which are part of the Isd iron-acquisition pathway. These findings aim to lay the groundwork for novel therapeutic approaches to combat drug-resistant pathogens.