9v49

Publication Abstract from PubMed

Xeruborbactam is a boronic acid-based transition-state analogue that has exhibited great potential as a clinically relevant inhibitor of carbapenemase enzymes, including class A carbapenemases. In this work, we have investigated the mechanism of inhibition of xeruborbactam against SME-1 carbapenemase using kinetic, structural, and thermodynamic approaches. With a K(i)(app) of 4 nM, xeruborbactam shows more potent inhibitory activity than any other beta-lactamase inhibitor available until now. Structural data from crystal complexes revealed that xeruborbactam covalently engages Ser70 at the active site and forms stabilizing interactions; in particular, the cyclopropyl group forms hydrophobic interactions with His105, further stabilizing the adduct, which correlates with a high rate of borylation and minimal deborylation. We investigated xeruborbactam with its 2R,3S-cyclopropyl isomer to grasp the influence of the stereochemistry of the cyclopropyl ring. Although both inhibitors bind covalently to Ser70 in SME-1, the 2R,3S-isomer adopts a different conformation of the cyclopropyl ring, which makes the C3 carbon much farther from His105, Asn132, and Lys73, thereby decreasing the binding affinity and K(i)(app) of the isomer. Furthermore, the fluorine-12 atom takes different conformations in the two structures, changing the terrain of interaction with the protein. Consistent with its lowered inhibition efficiency, the 2R,3S-isomer shows a lower borylation rate and weaker enzyme-inhibitor binding. In the molecular dynamics, xeruborbactam stabilized SME-1 more than its isomer, which is consistent with our experimental findings. These results together show the strong inhibitory profile of xeruborbactam and highlight the importance of stereochemistry in the design of next-generation beta-lactamase inhibitors and diagnostics for AMR.

Structural Insights into the Role of the Stereochemistry of the Cyclopropyl Ring in the Inhibitory Activity of Xeruborbactam against SME-1 Class A Carbapenemase.,Dhankhar K, S R Nair A, Hazra M, Alhmeidi Alkhatib AE, Baidya S, Mishra NC, Hazra S Biochemistry. 2025 Oct 7;64(19):4217-4231. doi: 10.1021/acs.biochem.5c00336. Epub , 2025 Sep 26. PMID:41002159^[4]

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