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Publication Abstract from PubMed

Class A beta-lactamases are a major cause of beta-lactam resistance in Gram-negative bacteria. The recent FDA approved cyclic boronate, vaborbactam, is a reversible covalent inhibitor of class A beta-lactamases including CTX-M extended-spectrum beta-lactamase and KPC carbapenemase, both frequently observed in the clinic. Intriguingly, vaborbactam displayed different binding kinetics and cell-based activity towards these two enzymes, despite their similarity. A 1.0 A crystal structure of CTX-M-14 demonstrates that two catalytic residues, K73 and E166, are positively charged and neutral, respectively. Meanwhile, a 1.25 A crystal structure of KPC-2 revealed a more compact binding mode of vaborbactam versus CTX-M-14, and alternative conformations of W105. Together with kinetic analysis of W105 mutants, the structures demonstrate the influence of this residue and the unusual conformation of the beta3 strand on the inactivation rate, and the stability of the reversible covalent bond with S70. Furthermore, studies of KPC-2 S130G mutant shed light on the different impacts of S130 in the binding of vaborbactam versus avibactam, another recently approved beta-lactamase inhibitor. Taken together, these new data provide valuable insights into the inhibition mechanism of vaborbactam and future development of cyclic boronate inhibitors.

Structural basis and binding kinetics of vaborbactam in class A beta-lactamase inhibition.,Pemberton OA, Tsivkovski R, Totrov M, Lomovskaya O, Chen Y Antimicrob Agents Chemother. 2020 Aug 10. pii: AAC.00398-20. doi:, 10.1128/AAC.00398-20. PMID:32778546^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.