Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase

Area of Science:

• Microbiology
• Infectious Diseases
• Drug Discovery

Background:

• Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of hospital-acquired infections, including surgical site infections, bacteremia, and sepsis.
• Antibiotic resistance in MRSA necessitates alternative treatment strategies, as conventional prophylaxis often fails or leads to secondary infections like Clostridium difficile.
• Sortase A, a key transpeptidase in Staphylococcus aureus, is crucial for anchoring surface proteins and is essential for virulence, as sortase mutants are avirulent in vivo.

Purpose of the Study:

• To identify and develop novel inhibitors targeting Sortase A as a potential anti-infective therapy for MRSA.
• To evaluate the efficacy of Sortase A inhibitors in vitro and in vivo against MRSA infections.

Main Methods:

• Utilized virtual screening and structure-based optimization to identify potential Sortase A inhibitors.
• Synthesized and tested lead compounds, including 3-(4-pyridinyl)-6-(2-sodiumsulfonatephenyl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole, for their ability to block sortase activity.
• Assessed the efficacy of Sortase A inhibitors in protecting mice against lethal Staphylococcus aureus bacteremia.

Main Results:

• Identified novel Sortase A inhibitors that effectively block enzyme activity in vitro and in vivo.
• Sortase A inhibitors demonstrated protection against lethal MRSA bacteremia in a mouse model.
• The identified inhibitors did not affect the in vitro growth of Staphylococcus aureus.

Conclusions:

• Sortase A inhibitors represent a promising therapeutic strategy for preventing hospital-acquired MRSA infections.
• This approach offers a potential alternative to antibiotics, mitigating risks of resistance and side effects associated with conventional treatments.
• Sortase inhibitors may be particularly beneficial for high-risk patients requiring prophylaxis against MRSA.