Sulfoximine Derivatives of Clinically Used Serine Beta lactamase Inhibitors With Improved Reactivity and Selectivity Profile
Combinations of Beta-lactam antibiotics and serine Beta-lactamase (SBL) inhibitors are widely used to counter resistance conferred by SBL hydrolysis; SBL inhibitors are increasingly subject to resistance. The penam-sulfone sulbactam inhibits SBLs by forming stable acyl-enzyme complexes (AECs) via opening of both its rings. Sulbactam has antibacterial activity and is used in combination with the SBL inhibitor durlobactam to treat Acinetobacter baumannii infections. We report on the rhodium mediated synthesis and activities of sulbactam-derived penam-sulfoximines. The sulfoximine N-substituents affect both chemical stability and SBL inhibition potency. Some sulbactam sulfoximine derivatives inhibited SBLs more efficiently than sulbactam via formation of stable AECs as shown by crystallography and mass spectrometry. When combined with durlobactam, the sulfoximine in which the pro-(S) sulfone oxygen of sulbactam was replaced with NH manifested superior antibacterial activity against several A. baumannii strains compared to sulbactam/durlobactam. The results reveal the potential of penam-sulfoximines as antibiotics and SBL inhibitors.