C6 Hydroxymethyl-Substituted Carbapenem MA-1-206 Inhibits the Major <i>Acinetobacter baumannii</i> Carbapenemase OXA-23 by Impeding Deacylation
Nichole K. Stewart, Márta Tóth, Maha A. Alqurafi, Weirui Chai, Thu Nguyen, Pojun Quan, Mijoon Lee, John D. Buynak, Clyde A. Smith, Sergei B. Vakulenko
Abstract
Carbapenem antibiotics are the drugs of choice for treatment of deadly infections caused by Gram-negative bacteria. However, their efficacy is severely compromised by the wide spread of carbapenem-hydrolyzing class D β-lactamases (CHDLs). The importance of this research is the discovery that substitution of the canonical hydroxyethyl group of carbapenems by a hydroxymethyl significantly enhances stability against inactivation by the major CHDL of Acinetobacter baumannii, OXA-23. These results provide a novel strategy for designing next-generation, carbapenemase-stable carbapenems to fight multidrug-resistant infections caused by Gram-negative pathogens.