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

Abstract

The number of infections caused by Gram-negative pathogens carrying carbapenemases is increasing, and the group of carbapenem-hydrolyzing class D β-lactamases (CHDLs) is especially problematic. Several clinically important CHDLs have been identified in , including OXA-23, OXA-24/40, OXA-58, OXA-143, OXA-235, and the chromosomally encoded OXA-51. The selection and dissemination of carbapenem-resistant strains constitutes a serious global threat. Carbapenems have been successfully utilized as last-resort antibiotics for the treatment of multidrug-resistant 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 The β-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 class D carbapenemases. Docking assays confirmed the affinity of LN-1-255 for the active site of these enzymes. LN-1-255 represents a potential new β-lactamase inhibitor that may have a significant role in eradicating infections caused by isolates carrying CHDLs.

Therapeutic Efficacy of LN-1-255 in Combination with Imipenem in Severe Infection Caused by Carbapenem-Resistant Acinetobacter baumannii

“…LN-1-255, a new ␤-lactamase inhibitor, is being developed to address growing carbapenemase resistance due to CHDLs. It has been previously shown to preserve imipenem activity against OXA-48-producing strains (17) and against the most relevant CHDLs of A. baumannii (10). Porin loss seems not to affect this inhibitor, probably due to its structural similarity with siderophores (17).…”

“…The combination of carbapenems with LN-1-255 led to an important decrease in the MICs of these antibiotics (10). Similarly, this inhibitor also demonstrated good inhibitory activity against the CHDL OXA-48, as assessed by both kinetic and microbiological studies (10,17). Other OXA or class A noncarbapenemase ␤-lactamases are also inhibited by this compound (19).…”

“…Since the inhibition potency of LN-1-255 against the major representative enzymes of all CHDL families described to date in A. baumannii has been previously demostrated by our group (10), in the present study we propose a new antimicrobial strategy. Therefore, the objective of this study is the evaluation of a new therapy combining imipenem and LN-1-255 for the treatment of an experimental murine pneumonia model caused by carbapenem-resistant A. baumannii transformants and clinical isolates carrying CHDLs.…”

“…Consequently, the production of ␤-lactamase enzymes is the most relevant mechanism of antibiotic inactivation through the cleavage of the ␤-lactam ring. The carbapenem-hydrolyzing class D ␤-lactamases (CHDLs), such as OXA-23 or OXA-24/40, are the most important carbapenemases produced by A. baumannii (6)(7)(8)(9)(10). The spread of OXA carbapenemases in the last decade is seriously compromising the use of these antibiotics, threatening the sustainability of carbapenem efficacy against A. baumannii.…”

“…Within a series of developed compounds, the compound LN-1-255 presented affinity in the nM range for all of the A. baumannii CHDLs tested, including the relevant OXA-23, OXA-24/40, OXA-58, and OXA-143 CHDLs (10,(16)(17)(18). The combination of carbapenems with LN-1-255 led to an important decrease in the MICs of these antibiotics (10). Similarly, this inhibitor also demonstrated good inhibitory activity against the CHDL OXA-48, as assessed by both kinetic and microbiological studies (10,17).…”