ABSTRACT
Novel antibacterial drugs that are effective against infections caused by multidrug resistant pathogens are urgently needed. In a previous report, we have shown that tetrahydropyran-based inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) display potent antibacterial activity and exhibit no target-mediated cross-resistance with fluoroquinolones. During the course of our optimization program, lead compound 5 was deprioritized due to adverse findings in cardiovascular safety studies. In the effort of mitigating these findings and optimizing further the pharmacological profile of this class of compounds, we have identified a subseries of tetrahydropyran-based molecules that are potent DNA gyrase and topoisomerase IV inhibitors and display excellent antibacterial activity against Gram positive pathogens, including clinically relevant resistant isolates. One representative of this class, compound 32d, elicited only weak inhibition of hERG K(+) channels and hNaV1.5 Na(+) channels, and no effects were observed on cardiovascular parameters in anesthetized guinea pigs. In vivo efficacy in animal infection models has been demonstrated against Staphylococcus aureus and Streptococcus pneumoniae strains.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Gram-Positive Bacteria/drug effects , Pyrans/chemical synthesis , Topoisomerase II Inhibitors/chemical synthesis , Animals , Anti-Bacterial Agents/pharmacology , Guinea Pigs , Hemodynamics/drug effects , Humans , Male , Mice , Microbial Sensitivity Tests , Pyrans/pharmacology , Rats , Rats, Wistar , Structure-Activity Relationship , Topoisomerase II Inhibitors/pharmacologyABSTRACT
There is an urgent need for new antibacterial drugs that are effective against infections caused by multidrug-resistant pathogens. Novel nonfluoroquinolone inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) have the potential to become such drugs because they display potent antibacterial activity and exhibit no target-mediated cross-resistance with fluoroquinolones. Bacterial topoisomerase inhibitors that are built on a tetrahydropyran ring linked to a bicyclic aromatic moiety through a syn-diol linker show potent anti-Gram-positive activity, covering isolates with clinically relevant resistance phenotypes. For instance, analog 49c was found to be a dual DNA gyrase-topoisomerase IV inhibitor, with broad antibacterial activity and low propensity for spontaneous resistance development, but suffered from high hERG K(+) channel block. On the other hand, analog 49e displayed lower hERG K(+) channel block while retaining potent in vitro antibacterial activity and acceptable frequency for resistance development. Furthermore, analog 49e showed moderate clearance in rat and promising in vivo efficacy against Staphylococcus aureus in a murine infection model.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , DNA Topoisomerases/metabolism , Drug Design , Gram-Positive Bacteria/drug effects , Pyrans/chemical synthesis , Pyrans/pharmacology , Animals , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacokinetics , Chemistry Techniques, Synthetic , DNA Gyrase/chemistry , DNA Gyrase/metabolism , DNA Topoisomerase IV/antagonists & inhibitors , DNA Topoisomerase IV/chemistry , DNA Topoisomerase IV/metabolism , DNA Topoisomerases/chemistry , Female , Gram-Positive Bacteria/enzymology , Humans , Inhibitory Concentration 50 , Mice , Molecular Docking Simulation , Protein Conformation , Pyrans/metabolism , Pyrans/pharmacokinetics , Rats , Structure-Activity Relationship , Topoisomerase II Inhibitors , Topoisomerase Inhibitors/chemical synthesis , Topoisomerase Inhibitors/metabolism , Topoisomerase Inhibitors/pharmacokinetics , Topoisomerase Inhibitors/pharmacologyABSTRACT
A series of 2-amino-[1,8]-naphthyridine-3-carboxamides (ANCs) with potent inhibition of bacterial NAD(+)-dependent DNA ligases (LigAs) evolved from a 2,4-diaminopteridine derivative discovered by HTS. The design was guided by several highly resolved X-ray structures of our inhibitors in complex with either Streptococcus pneumoniae or Escherichia coli LigA. The structure-activity-relationship based on the ANC scaffold is discussed. The in-depth characterization of 2-amino-6-bromo-7-(trifluoromethyl)-[1,8]-naphthyridine-3-carboxamide, which displayed promising in vitro (MIC Staphylococcus aureus 1 mg/L) and in vivo anti-staphylococcal activity, is presented.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , DNA Ligases/antagonists & inhibitors , Drug Design , Staphylococcus/drug effects , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/therapeutic use , Crystallography, X-Ray , DNA, Bacterial/antagonists & inhibitors , Inhibitory Concentration 50 , Mice , Microbial Sensitivity Tests , Molecular Structure , Rats , Staphylococcal Infections/drug therapy , Structure-Activity RelationshipABSTRACT
OBJECTIVES: In this study, the in vitro antimicrobial activity and spectrum of new dimeric compounds derived from the cyanobacterial alkaloid nostocarboline were investigated. The mechanism of action and selectivity to bacteria were studied and compared to the cationic antiseptic chlorhexidine. METHODS: Minimal inhibitory concentrations were determined against clinical isolates and against a panel of microbial reference strains using the CLSI microdilution method. Bacterial membrane damage was addressed by measuring ATP leakage and the mode of action was investigated in Escherichia coli reporter strains. Selectivity was tested by a cytotoxicity assay using MTS. RESULTS: The antimicrobial potency of dimers varied with length of the hydrophobic linker. The most potent compounds, NCD9 and NCD10, had a C10 and C12 linker, respectively, and showed strong activity against Gram-positive bacteria, notably methicillin-resistant Staphylococcus aureus strains. Similar to chlorhexidine, these compounds showed a rapid concentration-dependent bactericidal effect, which correlated with membrane damage as indicated by ATP leakage. NCD9, in contrast to NCD10 and chlorhexidine, lacked activity against yeast strains and showed low cytotoxicity in CHO cells indicating a high degree of selectivity. In E. coli reporter strains, NCD9 induced the DegP response pathway as well as the SOS response, suggesting interaction with both the cell envelope and DNA metabolism. CONCLUSIONS: The results presented in this report indicate the potential of this new class of cationic antimicrobial compounds for the design of potent and selective antibacterials with low cytotoxicity.
