ABSTRACT
NXL101 is one of a new class of quinoline antibacterial DNA gyrase and topoisomerase IV inhibitors showing potent activity against gram-positive bacteria, including methicillin- and fluoroquinolone-resistant strains. NXL101 inhibited topoisomerase IV more effectively than gyrase from Escherichia coli, whereas the converse is true of enzymes from Staphylococcus aureus. This apparent target preference is opposite to that which is associated with most fluoroquinolone antibiotics. In vitro isolation of S. aureus mutants resistant to NXL101 followed by cloning and sequencing of the genes encoding gyrase and topoisomerase IV led to the identification of several different point mutations within, or close to, the quinolone resistance-determining region (QRDR) of GyrA. However, the mutations were not those that are most frequently associated with decreased sensitivity to quinolones. A fluoroquinolone-resistant mutant variant of gyrase generated in vitro was highly resistant to inhibition by the fluoroquinolones ciprofloxacin and moxifloxacin but remained fully susceptible to inhibition by NXL101. Two mutant gyrases constructed in vitro, with mutations in gyrA engineered according to those most frequently found in S. aureus strains resistant to NXL101, were insensitive to inhibition by NXL101 and had a diminished sensitivity to ciprofloxacin and moxifloxacin. Certain combinations of mutations giving rise to NXL101 resistance and those giving rise to fluoroquinolone resistance may be mutually exclusive.
Subject(s)
Anti-Bacterial Agents/pharmacology , Enzyme Inhibitors/pharmacology , Escherichia coli/drug effects , Quinolines/pharmacology , Staphylococcus aureus/drug effects , Topoisomerase II Inhibitors , DNA Gyrase/genetics , DNA Topoisomerases, Type II/genetics , Drug Resistance, Bacterial/genetics , Escherichia coli/enzymology , Escherichia coli/genetics , Fluoroquinolones/pharmacology , Inhibitory Concentration 50 , Models, Molecular , Point Mutation , Staphylococcus aureus/enzymology , Staphylococcus aureus/geneticsABSTRACT
We have studied the protective effect of dexrazoxane on the cardiac toxicity induced by the anthracyclines currently used in clinics, doxorubicin, epirubicin, daunorubicin and idarubicin, with special emphasis on determining the optimal dose of dexrazoxane. This was performed using the model of isolated perfused rat heart after 12-day combination treatment of anthracyclines used at equi-cardiotoxic doses, and dexrazoxane used at 10-fold or 20-fold the anthracycline dose. We have shown in this study that dexrazoxane by itself was not cardiotoxic, and was able to significantly reduce anthracycline cardiac toxicity without increasing the general toxicity induced by these drugs. Using dexrazoxane at 20 times the anthracycline dose provided a better cardioprotection than using it at 10 times the anthracycline dose; at the higher dexrazoxane dose, the functional cardiac parameters (developed pressure, contractility and relaxation) were not different from those recorded in control animals.
Subject(s)
Anthracyclines/toxicity , Heart/drug effects , Razoxane/toxicity , Animals , Anthracyclines/administration & dosage , Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/toxicity , Dose-Response Relationship, Drug , Drug Interactions , Heart/physiopathology , In Vitro Techniques , Injections, Intraperitoneal , Male , Perfusion , Rats , Rats, Sprague-Dawley , Razoxane/administration & dosage , Toxicity Tests , Weight Gain/drug effects , Weight Loss/drug effectsABSTRACT
To new triterpenes, trichomycins A (1) and B (2), were purified from the new species Tricholoma sp. AU1 by activity-guided fractionation following their antibacterial activity. The two compounds were found to have a hitherto unreported triterpenoid skeleton. The structures and relative stereochemistry of 1 and 2 were determined through extensive 2D NMR spectroscopy, while the inhibitory activity of 1 and 2 against two Gram-positive and two Gram-negative bacteria and a mammalian cell line was determined.
Subject(s)
Anti-Bacterial Agents/isolation & purification , Basidiomycota/chemistry , Triterpenes/isolation & purification , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Australia , Drug Screening Assays, Antitumor , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Humans , Microbial Sensitivity Tests , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Triterpenes/chemistry , Triterpenes/pharmacology , Tumor Cells, CulturedABSTRACT
The formation of the Mtr2-Mex67 heterodimer is essential for yeast mRNA export as it constitutes a key nuclear component for shuttling mRNA between the nuclear and cytoplasm compartments through the nuclear pore complex. We report the crystal structures of apo-Mtr2 from the human pathogen Candida albicans and of its complex with the Mex67 NTF2-like domain. Compared with other members of the NTF2 fold family, Mtr2 displays novel structural features involved in the nuclear export of the large ribosomal subunit and consistent with a dual functional role of Mtr2 during yeast nuclear export events. The structure of the Mtr2-Mex67 NTF2-like domain complex, which overall is similar to those of the human and Saccharomyces cerevisiae homologs, unveils three putative Phe-Gly repeat binding sites, of which one contributes to the heterodimer interface. These structures exemplify an unrecognized adaptability of the NTF2 building block in evolution, identify novel structural determinants associated with key biological functions at the molecular surface of the yeast Mtr2-Mex67 complex, and suggest that the yeast and human mRNA export machineries may differ.
