How staphylococcus aureus ‘steals’ iron from our blood during infections

Researchers have revealed how Staphylococcus aureus bacteria extract iron from hemoglobin – a process crucial to their survival during infections. Using a novel time-resolved X-ray solution scattering (TR-XSS) technique, a research team at the ESRF, the European Synchrotron, Grenoble, France, has identified the full sequence of protein–protein interactions during this iron ‘theft’. The findings, published in Nature Communications, open possibilities for developing pharmaceuticals to combat antimicrobial-resistant strains of S. aureus.

Staphylococcus aureus is a common bacterium that lives harmlessly on the skin and nasal passages of many people. But occasionally it can breech surface barriers and immune defences, often through wounds, causing skin infections – which can lead to complications such as pneumonia or even life-threatening sepsis. Antibiotics are used routinely to tackle S. aureus infections, but some strains of this bacteria are increasingly resistant to existing drugs. Therefore, it is a priority to better understand how S. aureus survives and thrives in our bodies.

Now, experimental work at the ESRF has mapped in unprecedented detail how S. aureus bacteria acquire iron from our blood to aid its growth. Iron is an essential nutrient for S. aureus, which it can extract from the hemoglobin (Hb) in our red blood cells using a protein called IsdB. The process had been studied indirectly using optical methods. But nobody had mapped the complete sequence of molecular events with a technique able to directly probe transient structural changes of a protein.

Caught red-handed: taking the heme from hemoglobin 

The study focused on the dynamics of protein–protein interactions between IsdB and Hb. Scientists already knew that IsdB forms a complex to extract the iron-rich ‘heme’ component of Hb. To observe the process in closer detail, the researchers combined the techniques of Time-Resolved X-Ray Solution Scattering (TR-XSS) with rapid mixing. Unprecedented detail was revealed thanks to the use of short (20 μs) polychromatic X-ray pulses, and by collecting data up to the wide-angle X-ray scattering (WAXS) region.

The work was carried out by an Italian research team (University of Parma and University of Turin) at the ID09 Beamline in collaboration with ESRF scientist Matteo Levantino. The team developed a kinetic model able to describe the whole IsdB-Hb interaction process and found that IsdB extracts the heme only when both chains of Hb are bound to IsdB. From the point of view of the S. aureus, this appears to maximise the yield of extraction. Armed with this knowledge, pharmaceutical chemists can seek to develop drugs to interrupt the process. 

“Knowing the whole mechanism, it's easier to focus on a specific step that could be more effective at inhibiting the interactions,” says Luca Ronda from the University of Parma, part of the research team. Antimicrobial resistance remains a top global health concern, and methicillin-resistant Staphylococcus aureus (MRSA) has been flagged as a pathogen of public health importance by the World Health Organization.

New possibilities for studying dynamic protein structures

The TR-XSS technique can also be used to characterise biological systems involved in other diseases. It provides structural information useful in drug development, not limited to host-pathogen interaction, but also within the same living organism. For example, the reactions promoted by enzymes, which are biological catalysts that speed up the rate of reactions in our metabolism.

Other methods, such as optical spectroscopy and fluorescence, are used to study proteins interacting in many contexts.  But a limitation is that they are sensitive to the surroundings of specific spectroscopic probes and not to the entire structure of the protein. X-ray solution scattering, on the other hand, is sensitive to all the atoms in a target protein. “If a protein undergoes a global structural change, you cannot miss it,” says Levantino.