ABSTRACT
Antistaphylococcal agents commonly lack activity against Gram-negative bacteria like Escherichia coli owing to the permeability barrier presented by the outer membrane and/or the action of efflux transporters. When these intrinsic resistance mechanisms are artificially compromised, such agents almost invariably demonstrate antibacterial activity against Gram negatives. Here we show that this is not the case for the antibiotic daptomycin, whose target appears to be absent from E. coli and other Gram-negative pathogens.
Subject(s)
Anti-Bacterial Agents/pharmacology , Daptomycin/pharmacology , Escherichia coli/drug effects , Staphylococcus aureus/drug effects , Cell Membrane/drug effects , Cell Membrane/metabolism , Cell Membrane Permeability/drug effects , Enterobacter cloacae/drug effects , Enterobacter cloacae/growth & development , Enterobacter cloacae/metabolism , Escherichia coli/growth & development , Escherichia coli/metabolism , Klebsiella pneumoniae/drug effects , Klebsiella pneumoniae/growth & development , Klebsiella pneumoniae/metabolism , Microbial Sensitivity Tests , Moraxella catarrhalis/drug effects , Moraxella catarrhalis/growth & development , Moraxella catarrhalis/metabolism , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/growth & development , Pseudomonas aeruginosa/metabolism , Salmonella typhimurium/drug effects , Salmonella typhimurium/growth & development , Salmonella typhimurium/metabolism , Species Specificity , Staphylococcus aureus/growth & development , Staphylococcus aureus/metabolismABSTRACT
We further examined the usefulness of previously reported Bacillus subtilis biosensors for antibacterial mode-of-action studies. The biosensors could not detect the tRNA synthetase inhibitors mupirocin, indolmycin, and borrelidin, some inhibitors of peptidoglycan synthesis, and most membrane-damaging agents. However, the biosensors confirmed the modes of action of several RNA polymerase inhibitors and DNA intercalators and provided new insights into the possible modes of action of ciprofloxacin, anhydrotetracycline, corralopyronin, 8-hydroxyquinoline, and juglone.
Subject(s)
Anti-Bacterial Agents/pharmacology , Bacillus subtilis/drug effects , Biosensing Techniques , Amino Acyl-tRNA Synthetases/antagonists & inhibitors , Ciprofloxacin/pharmacology , Enzyme Inhibitors/pharmacology , Fatty Alcohols/pharmacology , Indoles/pharmacology , Mupirocin/pharmacology , Naphthoquinones/pharmacology , Oxyquinoline/pharmacology , Tetracyclines/pharmacologyABSTRACT
Bacterial RNA polymerase (RNAP) is essential for transcription and is an antibacterial target for small molecule inhibitors. The binding region of myxopyronin B (MyxB), a bacterial RNAP inhibitor, offers the possibility of new inhibitor design. The molecular design program SPROUT has been used in conjunction with the X-ray cocrystal structure of Thermus thermophilus RNAP with MyxB to design novel inhibitors based on a substituted pyridyl-benzamide scaffold. A series of molecules, with molecular masses <350 Da, have been prepared using a simple synthetic approach. A number of these compounds inhibited Escherichia coli RNAP.
ABSTRACT
Previous studies suggest that furanyl-rhodanines might specifically inhibit bacterial RNA polymerase (RNAP). We further explored three compounds from this class. Although they inhibited RNAP, each compound also inhibited malate dehydrogenase and chymotrypsin. Using biosensors responsive to inhibition of macromolecular synthesis and membrane damaging assays, we concluded that in bacteria, one compound inhibited DNA synthesis and another caused membrane damage. The third rhodanine lacked antibacterial activity. We consider furanyl-rhodanines to be unattractive RNAP inhibitor drug candidates.
