Activity of the beta-Lactamase Inhibitor LN-1-255 against Carbapenem-Hydrolyzing Class D beta-Lactamases from Acinetobacter baumannii

作者：Vazquez Ucha Juan Carlos; Maneiro Maria; Martinez Guitian Marta; Buynak John; Bethel Christopher R; Bonomo Robert A; Bou German; Poza Margarita; Gonzalez Bello Concepcion; Beceiro Alejandro^*

来源：Antimicrobial Agents and Chemotherapy, 2017, 61(11): e01172-17.

DOI：10.1128/AAC.01172-17

• beta-lactamase inhibitors
• Acinetobacter baumannii
• antimicrobial resistance
• carbapenem-hydrolyzing class D beta-lactamases

The number of infections caused by Gram-negative pathogens carrying carbapenemases is increasing, and the group of carbapenem-hydrolyzing class D beta-lactamases (CHDLs) is especially problematic. Several clinically important CHDLs have been identified in Acinetobacter baumannii, including OXA-23, OXA-24/40, OXA58, OXA-143, OXA-235, and the chromosomally encoded OXA-51. The selection and dissemination of carbapenem-resistant A. baumannii strains constitutes a serious global threat. Carbapenems have been successfully utilized as last-resort antibiotics for the treatment of multidrug-resistant A. baumannii infections. However, the spread of OXA carbapenemases is compromising the continued use of these antimicrobials. In response to this clinical issue, it is necessary and urgent to design and develop new specific inhibitors with efficacy against these enzymes. The aim of this work was to characterize the inhibitory activity of LN-1-255 (a 6-alkylidene-2-substituted penicillin sulfone) and compare it to that of two established inhibitors (avibactam and tazobactam) against the most relevant enzymes of each group of class D carbapenemases in A. baumannii. The beta-lactamase inhibitor LN-1-255 demonstrated excellent microbiological synergy and inhibition kinetics parameters against all tested CHDLs and a significantly higher activity than tazobactam and avibactam. A combination of carbapenems and LN-1-255 was effective against A. baumannii class D carbapenemases. Docking assays confirmed the affinity of LN-1255 for the active site of these enzymes. LN-1-255 represents a potential new beta-lactamase inhibitor that may have a significant role in eradicating infections caused by A. baumannii isolates carrying CHDLs.

• 出版日期2017-11