Staphylococcus aureus is a Gram-positive bacterium that causes infections in various parts of the body. Methicillin-resistant Staphylococcus aureus (MRSA) strains have become increasingly dangerous and life threatening to human health due to widespread resistance. They are responsible for a wide variety of infectious diseases such as skin infections, bloodstream infections, and surgical wound infections etc1., The VraS/VraR two component regulatory system2 plays a crucial role in developing several resistance genes such as PBP2a encoded by mecA and thus develops resistance to b-lactam antibiotics including methicillin and oxacillin. The VraS is a membrane histidine kinase, that has ATP binding domain which is conserved with the ATPase domain of eukaryotic Hsp90 molecular chaperones3. Therefore, small molecule mammalian protein kinases could be used to inhibit bacterial histidine kinases and thus potentiate antibiotic activity. Recently, Striker et al., reported that the pyrazolopyridazine GW779439X synergies oxacillin in methicillin-resistant Staphylococcus aureus (MRSA) through inhibition of the PASTA kinase Stk14. Herein, we have screened ATP competitive inhibitors from focus biomolecules highly selective kinase inhibitor library and selected Tofactinib5 which was found to bind VraS weakly by surface plasmon resonance. Using this scaffold, we synthesized fifty analogs and tested them against MRSA USA 300 strain in the presence of oxacillin using checkerboard assays. A clear structure activity relationship was developed with fifteen compounds showing strong synergy. The best compound 4223 exhibits a 16-fold decrease in oxacillin MIC at 12.5 mg/mL concentration. It is important to note that these small molecules did not show any antibiotic activity on their own, indicating that only lowering the MIC value for oxacillin by blocking the antibiotic stress response network.

Small molecule potentiators for oxacillin against methicillin-resistant Staphylococcus

ACS Spring 2022

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