Understanding heme stress sensing system by pathogens, to design new antibiotics – HemeDetox

Heme (the blood hemoglobin cofactor) is a vital but toxic molecule for all organisms. When numerous Gram-positive pathogens are confronted with blood-heme toxicity during infection, they respond by inducing expression of HrtBA, a heme efflux transporter. hrtBA is regulated by HssRS (Heme sensing system), a two-component system (TCS) comprising HssS, a membrane exogenous heme sensor, and HssR, a transcriptional regulator of hrtBA. As heme-engorged bacteria are attenuated for virulence, blocking the heme-dependent HssS response inhibition would limit infection within their host. This strategy constitutes the “HemeDetox” working hypothesis.
The two major Gram-positive pathogens, Staphylococcus aureus and Streptococcus agalactiae (referred to as GBS for Group B Streptococcus), use an HrtBA efflux pump for heme homeostasis. HrtBA expression is regulated by HssSSA in S. aureus and by HssSGBS, in GBS, which share 30% identity. Unexpectedly, our experimental findings established that unlike most TCS sensors, HssS is activated by internalized heme rather than the extracellular molecule. Furthermore, in silico and experimental data suggest that HssSSA responds to intracytoplasmic heme, whereas HssSGBS responds to membrane-embedded-heme.
The “HemeDetox” project objectives are to: (i) elucidate the mechanisms of HssS activation in S. aureus and GBS; (ii) screen a chemical library for S. aureus HssS heme activation inhibitors.
Scientific pertinence and impact of the “HemeDetox” project:
Mechanistic- The complementary “HemeDetox” consortium will use integrated biochemistry, crystallography and cell microbiology approaches to unravel heme-bound HssS structure and fine mechanisms underlying HssS activation in S. aureus and GBS.
Concept- Findings from this project may establish a new paradigm for bacterial adaptation, by showing that the highly conserved signaling pathway leading to heme efflux and its cognate regulator have evolved distinct ligand recognition strategies according to bacterial species lifestyles.
Application- In view of the health threat posed by S. aureus and the demonstrated importance of heme toxicity management in virulence, a specific block of HssSSA heme signaling could constitute an original and efficient approach to limit S. aureus adaptive capacity within the host. Design of a high-throughput 2-step approach will be facilitated by structural and physiological results obtained in the frame of this project.