Avibactam Sodium

Avibactam sodium and its free acid, avibactam, are diazabicyclooctane (DBO)–based, non-β-lactam β-lactamase inhibitors (BLIs) that are used to treat multi-drug–resistant Gram-negative bacterial pathogens. The compounds were jointly developed by Actavis Generics (now part of Teva Pharmaceutical Industries) and AstraZeneca.  

In 2015, avibactam sodium, in combination with ceftazidime, a cephalosporin antibiotic, was approved by the US Food and Drug Administration. The dual-drug’s target was complex urinary tract and intra-abdominal infections caused by Gram-negative, often hospital-acquired, bacteria.

Last year, in the continuing quest to combat multi-drug–resistant bacteria, Eric M. Gordon, Matthew A. J. Duncton, and Mark A. Gallop at Arixa Pharmaceuticals (Palo Alto, CA) prepared analogues of avibactam that are more orally available than the free acid or its salt. (Currently, avibactam can be administered only intravenously; the only orally available BLI on the market is the less useful clavulanic acid.)

The researchers prepared prodrugs of avibactam in which various moieties form esters of the sulfate group. (Historically, charged sulfate groups on drug molecules were seen as strong obstacles to oral bioavailability.) The derivatives with the highest oral availabilities to laboratory animals had a quaternary carbon atom in the β position of the added sulfate ester and a carboxylate ester as one of the substituents on the quaternary carbon (i.e., –OSO₃–CH₂–CR¹R²–CO₂R³).

The authors believe that their avibactam analogues are orally available because of steric hindrance to hydrolysis provided by the sulfate ester and the gem-disubstituent/trimethyl lock effect that brings the carboxylate nucleophile closer to the eventual displacement site. In a simulation of in vivo conditions, they demonstrated that the prodrug can be cleaved under mild conditions to release the unesterified avibactam.