ABSTRACT
Metallo-ß-lactamases (MBLs), such as New Delhi metallo-ß-lactamase (NDM-1) have spread world-wide and present a serious threat. Expression of MBLs confers resistance in Gram-negative bacteria to all classes of ß-lactam antibiotics, with the exception of monobactams, which are intrinsically stable to MBLs. However, existing first generation monobactam drugs like aztreonam have limited clinical utility against MBL-expressing strains because they are impacted by serine ß-lactamases (SBLs), which are often co-expressed in clinical isolates. Here, we optimized novel monobactams for stability against SBLs, which led to the identification of LYS228 (compound 31). LYS228 is potent in the presence of all classes of ß-lactamases and shows potent activity against carbapenem-resistant isolates of Enterobacteriaceae (CRE).
Subject(s)
Anti-Bacterial Agents/pharmacology , Bacterial Proteins/metabolism , Carbapenem-Resistant Enterobacteriaceae/drug effects , Monobactams/pharmacology , beta-Lactam Resistance/drug effects , beta-Lactamases/metabolism , Animals , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/metabolism , Aztreonam/pharmacology , CHO Cells , Cricetulus , Drug Stability , Escherichia coli/drug effects , Female , Humans , Meropenem , Mice , Microbial Sensitivity Tests , Molecular Structure , Monobactams/adverse effects , Monobactams/chemistry , Monobactams/metabolism , Pseudomonas aeruginosa/drug effects , Receptors, GABA-A/metabolism , Seizures/chemically induced , Structure-Activity Relationship , Thienamycins/pharmacologyABSTRACT
Histone deacetylase (HDAC) inhibitors have shown promise in treating various forms of cancer. However, many HDAC inhibitors from diverse structural classes have been associated with QT prolongation in humans. Inhibition of the human ether a-go-go related gene (hERG) channel has been associated with QT prolongation and fatal arrhythmias. To determine if the observed cardiac effects of HDAC inhibitors in humans is due to hERG blockade, a highly potent HDAC inhibitor devoid of hERG activity was required. Starting with dacinostat (LAQ824), a highly potent HDAC inhibitor, we explored the SAR to determine the pharmacophores required for HDAC and hERG inhibition. We disclose here the results of these efforts where a high degree of pharmacophore homology between these two targets was discovered. This similarity prevented traditional strategies for mitigating hERG binding/modulation from being successful and novel approaches for reducing hERG inhibition were required. Using a hERG homology model, two compounds, 11r and 25i, were discovered to be highly efficacious with weak affinity for the hERG and other ion channels.