Open AccessInhibition of the Clostridioides difficile Class D β-Lactamase CDD-1 by Avibactam
Author(s) -
Nichole K. Stewart,
Márta Tóth,
Anastasiya Stasyuk,
Mijoon Lee,
Clyde A. Smith,
Sergei B. Vakulenko
Publication year - 2021
Publication title -
acs infectious diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.324
H-Index - 39
ISSN - 2373-8227
DOI - 10.1021/acsinfecdis.0c00714
Subject(s) - clostridioides , avibactam , medicine , biology , genetics , bacteria , ceftazidime , pseudomonas aeruginosa
Avibactam is a potent diazobicyclooctane inhibitor of class A and C β-lactamases. The inhibitor also exhibits variable activity against some class D enzymes from Gram-negative bacteria; however, its interaction with recently discovered class D β-lactamases from Gram-positive bacteria has not been studied. Here, we describe microbiological, kinetic, and mass spectrometry studies of the interaction of avibactam with CDD-1, a class D β-lactamase from the clinically important pathogen Clostridioides difficile , and show that avibactam is a potent irreversible mechanism-based inhibitor of the enzyme. X-ray crystallographic studies at three time-points demonstrate the rapid formation of a stable CDD-1-avibactam acyl-enzyme complex and highlight differences in the anchoring of the inhibitor by class D enzymes from Gram-positive and Gram-negative bacteria.