Carbapenem-hydrolyzing class D beta-lactamase (CHDL)

Carbapenem-hydrolyzing class D beta-lactamases (CHDLs), also known as OXA-type carbapenemases, are a critical group of bacterial enzymes that confer high-level resistance to carbapenems, which are often considered antibiotics of last resort [7, 10]. These enzymes belong to the Ambler Class D serine beta-lactamases and utilize a unique catalytic mechanism involving a post-translationally carbamylated lysine residue to activate an active-site serine for the hydrolysis of the beta-lactam ring [5, 18]. CHDLs are primarily found in Gram-negative pathogens such as Acinetobacter baumannii (e.g., OXA-23, OXA-24/40) and Enterobacteriaceae (e.g., OXA-48), where they are frequently encoded on mobile genetic elements like plasmids, facilitating rapid global dissemination [12, 19]. While they characteristically show weak hydrolytic activity against some cephalosporins, their ability to inactivate carbapenems makes them a major clinical threat, especially when combined with other resistance mechanisms like porin loss or efflux pump overexpression [13, 23]. Therapeutically, these enzymes are targets for next-generation non-beta-lactam inhibitors, such as diazabicyclooctanes (avibactam, durlobactam) and boronates (taniborbactam), which aim to restore the efficacy of partner carbapenem or cephalosporin antibiotics [6, 15, 21].

Other names

OXA-type carbapenemaseClass D carbapenemaseCarbapenem-hydrolyzing oxacillinaseOxacillinase-type beta-lactamaseCHDLAmbler Class D beta-lactamase

Inhibitors target these enzymes through covalent binding to the active-site serine, either forming a stable carbamoyl-enzyme intermediate (diazabicyclooctanes) or mimicking the tetrahedral transition state (boronates), thereby preventing the enzyme from hydrolyzing partner beta-lactam antibiotics.