New drug compounds restore power of last-resort antibiotics against resistant bacteria
Researchers have designed fluorinated molecules that revive the effectiveness of meropenem, a critical antibiotic, against drug-resistant bacteria that cause difficult-to-treat infections. The compounds reduce bacterial resistance up to 64-fold, offering a potential near-term strategy to extend the clinical life of existing antibiotics while new drugs remain in development.
Originaltitel: Fluorinated captopril analogues inhibit metallo-ll-lactamases and facilitate structure determination of NDM-1 binding pose
<p>Bacterial resistance to the majority of clinically used ll-lactam antibiotics is a global health threat and, consequently, the driving force for the development of metallo-ll-lactamase (MBL) inhibitors. The rapid evolution of new MBLs calls for new strategies and tools for inhibitor development. In this study, we designed and developed a series of trifluoromethylated captopril analogues as probes for structural studies of enzyme-inhibitor binding. The new compounds showed activity comparable to the non-fluorinated inhibitors against the New Delhi Metallo-ll-lactamase-1 (NDM-1). The most active compound, a derivative of D-captopril, exhibited an IC50 value of 0.3 mu M. Several compounds demonstrated synergistic effects, restoring the effect of meropenem and reducing the minimum inhibitory concentration (MIC) values in NDM-1 (up to 64-fold), VIM-2 (up to 8-fold) and IMP-26 (up to 8-fold) harbouring Escherichia coli. NMR spectroscopy and molecular docking of one representative inhibitor determined the binding pose in NDM-1, demonstrating that fluorinated analogues of inhibitors are a valuable tool for structural studies of MBL-inhibitor complexes.</p>