Antibiotic resistance in bacterial pathogens is one of the major threats regarding human health. An alarming trend is the spread of metallo-β-lactamases (MBLs) among gram-negative pathogens that transfer resistance against almost all β-lactam antibiotics including carbapenems. The development of new anti-infective agents remains one of the most significant demands in modern medicine.
In this webinar we show the development of an assay platform consisting of three orthogonal assays: a fluorescence-based functional assay, thermal shift assay and in cell antimicrobial susceptibility testing. The reliability of the system was evaluated on three different class B MBLs: New-Delhi-Metallo-β-Lactamase-1 (NDM-1), Verona-Integron-Encoded-Metallo-β-Lactamase 1 (VIM-1) and Impenemase-7 (IMP-7).
The aim of this work is to find an already approved drug which restores the activity of β-lactam antibiotic by protecting it from hydrolysis through the MBL. We could find four drugs, which inhibit three clinically important MBLs, namely Captopril, Thiorphan, Dimercaprol and Tiopronin. This is a good starting point for the development of potent MBL inhibitors, with the primary optimization goal being the uptake and activity in pathogens. This will be modeled in SeeSAR.
