Disulfiram enhances meropenem activity against NDM- and IMP-producing carbapenem-resistantAcinetobacter baumanniiinfections

Abstract

Objectives To evaluate the in vitro and in vivo efficacy of the FDA-approved drug disulfiram in combination with meropenem against MBL-expressing carbapenem-resistant Acinetobacter baumannii. Methods Chequerboard and antibiotic resistance reversal analysis were performed using 25 clinical isolates producing different MBLs. Three representative strains harbouring NDM, IMP or non-MBL genes were subjected to a time–kill assay to further evaluate this synergistic interaction. Dose-dependent inhibition by disulfiram was assessed to determine IC50 for NDM-1, IMP-7, VIM-2 and KPC-2. Further, to test the efficacy of meropenem monotherapy and meropenem in combination with disulfiram against NDM- and IMP-harbouring A. baumannii, an experimental model of systemic infection and pneumonia was developed using BALB/c female mice. Results Chequerboard and antibiotic reversal assay displayed a synergistic interaction against MBL-expressing A. baumannii strains with 4- to 32-fold reduction in MICs of meropenem. In time–kill analysis, meropenem and disulfiram exhibited synergy against NDM- and IMP-producing carbapenem-resistant A. baumannii (CRAb) isolates. In vitro dose-dependent inhibition analysis showed that disulfiram inhibits NDM-1 and IMP-7 with IC50 values of 1.5 ± 0.6 and 16.25 ± 1.6 μM, respectively, with slight or no inhibition of VIM-2 (<20%) and KPC-2. The combination performed better in the clearance of bacterial load from the liver and spleen of mice infected with IMP-expressing CRAb. In the pneumonia model, the combination significantly decreased the bacterial burden of NDM producers compared with monotherapy. Conclusions These results strongly suggest that the combination of disulfiram and meropenem represents an effective treatment option for NDM- and IMP-associated CRAb infections.

Disulfiram: Mechanisms, Applications, and Challenges

“…Disulfiram enhances polymyxin B’s activity against Klebsiella pneumoniae both in vitro and in vivo [ 80 ]. It also demonstrates synergy with meropenem against MBL-expressing carbapenem-resistant Acinetobacter baumannii infections, lowering meropenem’s MIC by 4- to 32-fold [ 81 ]. One explanation for disulfiram’s efficacy against drug-resistant, Gram-negative species may be its activity against New Delhi metallo-beta-lactamase 1 (NDM-1), an enzyme that confers beta-lactam resistance to many such species.…”

Chemical genetic approaches for the discovery of bacterial cell wall inhibitors

“…114,115 The ever-emerging antibiotic resistance in clinics and the importance of cell wall drug targets warrant the discovery of novel bacterial cell wall inhibitors. [116][117][118] However, the target-based approach in discovering cell wall antibacterials becomes unfavourable when the inhibitors fail to act in vivo after showing promising inhibitory activity in vitro. 119 Hence, it is required to incorporate both cellbased screens (phenotypic screens) and target-based approaches in discovering bacterial cell wall inhibitors to overcome the challenges independently posed by phenotypic and target-based approaches.…”