ABSTRACT
A paucity of novel acting antibacterials is in development to treat the rising threat of antimicrobial resistance, particularly in Gram-negative hospital pathogens, which has led to renewed efforts in antibiotic drug discovery. Fluoroquinolones are broad-spectrum antibacterials that target DNA gyrase by stabilizing DNA-cleavage complexes, but their clinical utility has been compromised by resistance. We have identified a class of antibacterial thiophenes that target DNA gyrase with a unique mechanism of action and have activity against a range of bacterial pathogens, including strains resistant to fluoroquinolones. Although fluoroquinolones stabilize double-stranded DNA breaks, the antibacterial thiophenes stabilize gyrase-mediated DNA-cleavage complexes in either one DNA strand or both DNA strands. X-ray crystallography of DNA gyrase-DNA complexes shows the compounds binding to a protein pocket between the winged helix domain and topoisomerase-primase domain, remote from the DNA. Mutations of conserved residues around this pocket affect activity of the thiophene inhibitors, consistent with allosteric inhibition of DNA gyrase. This druggable pocket provides potentially complementary opportunities for targeting bacterial topoisomerases for antibiotic development.
Subject(s)
Anti-Bacterial Agents , DNA Cleavage , DNA Gyrase , Thiophenes , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/metabolism , Crystallography, X-Ray , DNA Gyrase/chemistry , DNA Gyrase/metabolism , Drug Discovery , Models, Molecular , Thiophenes/chemistry , Thiophenes/metabolismABSTRACT
During the course of our research on the lead optimisation of the NBTI (Novel Bacterial Type II Topoisomerase Inhibitors) class of antibacterials, we discovered a series of tricyclic compounds that showed good Gram-positive and Gram-negative potency. Herein we will discuss the various subunits that were investigated in this series and report advanced studies on compound 1 (GSK945237) which demonstrates good PK and in vivo efficacy properties.
Subject(s)
Anti-Bacterial Agents/pharmacology , Heterocyclic Compounds, 3-Ring/pharmacology , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Topoisomerase II Inhibitors/chemistry , Topoisomerase II Inhibitors/pharmacology , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacokinetics , Chemistry Techniques, Synthetic , DNA Topoisomerases, Type II/chemistry , DNA Topoisomerases, Type II/metabolism , Dogs , Drug Evaluation, Preclinical/methods , ERG1 Potassium Channel/metabolism , Gram-Negative Anaerobic Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemistry , Pneumococcal Infections/drug therapy , Rats , Respiratory Tract Infections/drug therapy , Respiratory Tract Infections/microbiology , Topoisomerase II Inhibitors/pharmacokineticsABSTRACT
Peptide deformylase (PDF), a clinically unexploited antibacterial target, plays an essential role in protein maturation. PDF inhibitors, therefore, represent a new antibiotic class with a unique mode of action that provides an alternative therapy for the treatment of infections caused by drug-resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). GSK1322322 is a novel PDF inhibitor that is in phase II clinical development for the treatment of lower respiratory tract and skin infections. We have discovered that PDF inhibitors can prevent S. aureus in vitro growth for up to 6 h at concentrations 8- to 32-fold below their MICs. This phenomenon seems specific to PDF inhibitors, as none of the antimicrobial agents with alternative mechanisms of action tested show such a potent and widespread effect. It also appears limited to S. aureus, as PDF inhibitors do not show such an inhibition of growth at sub-MIC levels in Streptococcus pneumoniae or Haemophilus influenzae. Analysis of the effect of GSK1322322 on the early growth of 100 randomly selected S. aureus strains showed that concentrations equal to or below 1/8× MIC inhibited growth of 91% of the strains tested for 6 h, while the corresponding amount of moxifloxacin or linezolid only affected the growth of 1% and 6% of strains, respectively. Furthermore, the sub-MIC effect demonstrated by GSK1322322 appears more substantial on those strains at the higher end of the MIC spectrum. These effects may impact the clinical efficacy of GSK1322322 in serious infections caused by multidrug-resistant S. aureus.
Subject(s)
Anti-Bacterial Agents/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Enzyme Inhibitors/pharmacology , Hydroxamic Acids/pharmacology , Staphylococcus aureus/drug effects , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity TestsABSTRACT
During the course of our research to find novel mode of action antibacterials, we discovered a series of hydroxyl tricyclic compounds that showed good potency against Gram-positive and Gram-negative pathogens. These compounds inhibit bacterial type IIA topoisomerases. Herein we will discuss structure-activity relationships in this series and report advanced studies on compound 1 (GSK966587) which demonstrates good PK and in vivo efficacy properties. X-ray crystallographic studies were used to provide insight into the structural basis for the difference in antibacterial potency between enantiomers.
Subject(s)
Bacteria/enzymology , Naphthyridines/chemistry , Naphthyridines/pharmacology , Topoisomerase II Inhibitors/chemistry , Topoisomerase II Inhibitors/pharmacology , Animals , Crystallography, X-Ray , Dogs , Enzyme Activation/drug effects , Haplorhini , Humans , Microbial Sensitivity Tests , Molecular Structure , RatsABSTRACT
We have identified a series of amino-piperidine antibacterials with a good broad spectrum potency. We report the investigation of various subunits in this series and advanced studies on compound 8. Compound 8 possesses good pharmacokinetics, broad spectrum antibacterial activity and demonstrates oral efficacy in a rat lung infection model.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , DNA Topoisomerases, Type II/chemistry , Dioxanes/chemistry , Dioxanes/pharmacology , Naphthyridines/chemistry , Naphthyridines/pharmacology , Piperidines/chemistry , Topoisomerase II Inhibitors/chemistry , Animals , Anti-Bacterial Agents/therapeutic use , DNA Topoisomerases, Type II/metabolism , Dioxanes/therapeutic use , Disease Models, Animal , Dogs , Haplorhini , Humans , Lung Diseases/drug therapy , Microbial Sensitivity Tests , Naphthyridines/therapeutic use , Piperidines/pharmacology , Piperidines/therapeutic use , Rats , Structure-Activity Relationship , Topoisomerase II Inhibitors/pharmacology , Topoisomerase II Inhibitors/therapeutic useABSTRACT
As part of our wider efforts to exploit novel mode of action antibacterials, we have discovered a series of cyclohexyl-amide compounds that has good Gram positive and Gram negative potency. The mechanism of action is via inhibition of bacterial topoisomerases II and IV. We have investigated various subunits in this series and report advanced studies on compound 7 which demonstrates good PK and in vivo efficacy properties.
Subject(s)
Amides/chemistry , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , DNA Topoisomerases, Type II/chemistry , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Topoisomerase II Inhibitors/chemistry , Amides/chemical synthesis , Amides/pharmacokinetics , Animals , Anti-Bacterial Agents/chemical synthesis , Binding Sites , Computer Simulation , DNA Topoisomerases, Type II/metabolism , Dogs , Haplorhini , Humans , Microbial Sensitivity Tests , Protein Structure, Tertiary , Rats , Structure-Activity Relationship , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/pharmacokineticsABSTRACT
We developed a homogenous microtiter based assay using the cationic dye 3, 3'-Diethyloxacarbocyanine iodide, DiOC2(3), to measure the effect of compounds on membrane potential in Staphylococcus aureus. In a screen of 372 compounds from a synthetic compound collection with anti-Escherichia coli activity due to unknown modes of action at least 17% demonstrated potent membrane activity, enabling rapid discrimination of nuisance compounds.
