ALBA Synchrotron
A study, published in the cover of the April issue of Nature Chemical Biology, has designed a compound that prevents the activation of resistance in the bacterium Staphylococcus aureus. This discovery, tested in mice, is a significant advance in the fight against infections caused by this pathogen, which has a very high incidence in hospitals. The research, led by the Blas Cabrera Institute of Physical Chemistry CSIC and the University of Notre Dame (USA), used data obtained at the XALOC beamline at the ALBA Synchrotron.
Scientists from the Blas Cabrera Institute of Physical Chemistry (IQF-CSIC) and the University of Notre Dame (Indiana, USA) identified a compound that blocks the bacteria's ability Staphylococcus aureus to survive antibiotics.
This pathogen is considered a superbug due to its ability to develop mechanisms that allow it to evade the action of multiple antibiotics, a phenomenon known as resistance, and which makes it difficult to treat infections, ranging from skin illnesses to pneumonia and septicemia, some of them potentially letal.
In particular, strains of Staphylococcus aureus resistant to antibiotic methicillin (MRSA) are especially problematic because they have spread their resistance to a wide range of antibiotics, making them difficult to fight against, especially in hospital.
This new compound, now synthesized and named compound 4, based on benzimidazole and commonly used against gastrointestinal parasites and fungi, has been selected from among 11 million candidate molecules for its ability to block a key protein of this pathogen, called BlaR1, that triggers the mechanism that inactivates antibiotics.
The combination of compound 4 along with the antibiotics oxacillin and meropenem has been shown effective in blocking the bacteria's resistance mechanism and ending the infection in mouse models, thus validating the potential of this novel therapeutic strategy as a model for developing similar therapies against other resistant bacteria.
X-ray crystallography at ALBA
XALOC beamline, ALBA Synchrotron
A highlight of this work is the use of X-ray crystallography at the XALOC beamline at the ALBA Synchrotron. Synchrotron light enabled to determine the structure of the BlaR1 protein bound to the inhibitor compound. This structural analysis revealed that compound 4 binds to the active site of BlaR1, providing crucial information about the inhibitor's mechanism of action and guiding the future design of targeted therapies.
Researchers have reached a preclinical stage testing compound 4, after verifying that it works in 40 strains of Staphylococcus aureus resistant on mice, where it has proven very effective. "The next step would be to move on to the clinical stage, where developments can already be made in humans and improve the pharmacokinetic properties,” explains Juan Hermoso.
This finding represents a significant advance in the fight against MRSA strain infections, as it offers a way to reuse β-lactam antibiotics such as penicillin, which were previously ineffective against these multi-resistant strains. In this sense, the study can help in expanding the available therapeutic options. This would improve clinical outcomes in patients affected by these difficult-to-treat infections and would reduce the need of last-resort antibiotics, such as vancomycin or linezolid, which helps maintain their effectiveness and reduce treatment costs.
The antibiotic resistance is one of the main threats to public health worldwide and compromises the ability to prevent and treat infectious diseases, putting medical procedures such as surgeries at risk and increasing mortality, according to the World Health Organization. In Europe, MRSA is one of the main causes of hospital infections that generate serious complications. It is estimated that around 10% of hospital-acquired infections in the region are caused by this resistant bacteria. In the United States, the problem is equally alarming, with more than 119,000 cases of infection in 2017 and more than 20,000 deaths annually related to this pathogen.
XALOC beamline has been upgraded recently with the purchase of new equipment that enable users to better prepare their experiments. These investments have been possible thanks to ICTS2022 grant funded by the Recovery, Transformation and Resilience Plan within the framework of the NextGenerationEU.