[SCAN] Structural and functional insights into hydrogen sulfide homeostasis in pathogenic bacteria

Title: Structural and functional insights into hydrogen sulfide homeostasis in pathogenic bacteria

Speaker: José A. Brito

Abstract: Hydrogen sulfide (H2S) is an ancient molecule present in Earth’s primordial atmosphere and organisms from all Domains of Life soon evolved to utilize it in their physiology. However, H2S can have either beneficial or toxic effects, depending on the concentration. Therefore, tight regulation of intracellular H2S and H2S-derived more oxidized reactive sulfur species (RSS) is paramount for survival of all organisms.

In bacterial pathogens, H2S/RSS is regarded as an important component in microbial defense mechanisms against oxidative and antibiotic stress, with recent studies highlighting a correlation of endogenous H2S and antibiotic resistance in Staphylococcus aureus and Bacillus anthracis. Moreover, H2S has been shown to revert intrinsic cephalosporin resistance in Enterococcus faecalis.

We have been studying the cst (copper-sensing operon repressor-like sulfurtransferase) operon in S. aureus and E. faecalis which encodes a nearly complete mitochondrial-like H2S oxidation system (S2- to thiosulfate, S2O32-). Three enzymes encoded by these two operons include the coenzyme A persulfide reductase CoAPR, the staphylococcal multidomain persulfide dioxygenase-sulfurtransferase fusion protein CstB, and the sulfide:quinone oxidoreductase SQR, which collectively protect the organism against H2S and RSS toxicity.

In this SCAN, we will describe the X-ray crystallographic structures of full-length SaCstB (native and single cysteine substitution mutants) and the CoA-bound crystal structure of EfCoAPR. These studies provide an enhanced understanding of the mechanisms of H2S/RSS homeostasis encoded by the RSS-regulated cst operons in pathogenic bacteria, leading to a deeper understanding of antimicrobial resistance. Ultimately, in a structure-based drug design approach, this will help us launch a counter-offensive against these human pathogens that threaten our ability to effectively treat common infections.

Keywords: hydrogen sulfide, sulfur-metabolising pathways, pathogenic bacteria, X-ray crystallography, cryo-EM