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 superbugdue 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.
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.
Read more on ALBA website
Image: Resistant ‘Staphylococcus aureus’ causes serious hospital infections, such as sepsis.
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