ABSTRACT
The synthesis and antibacterial activity of benzo[f][1,7]naphtyridone derivatives are reported. These compounds are potent antibacterial agents with a Gram-positive spectrum of activity. They are active against multi-resistant cocci, especially Staphylococcus aureus strains. Their physico-chemical and biological properties make them particularly suitable for topical antibacterial use.
Subject(s)
Anti-Infective Agents, Local/chemical synthesis , Anti-Infective Agents, Local/pharmacology , Gram-Positive Bacteria/drug effects , Naphthyridines/chemical synthesis , Naphthyridines/pharmacology , Chemical Phenomena , Chemistry, Physical , Drug Resistance, Multiple, Bacterial , Microbial Sensitivity Tests , Staphylococcus aureus/drug effects , Streptococcus pyogenes/drug effects , Structure-Activity RelationshipABSTRACT
The mechanism of resistance to the streptogramin antibiotics quinupristin and dalfopristin was studied in a Staphylococcus aureus clinical isolate selected under quinupristin-dalfopristin therapy, in four derivatives of S. aureus RN4220 selected in vitro, and in a mutant selected in a model of rabbit aortic endocarditis. For all strains the MICs of erythromycin, quinupristin, and quinupristin-dalfopristin were higher than those for the parental strains but the MICs of dalfopristin and lincomycin were similar. Portions of genes for domains II and V of 23S rRNA and the genes for ribosomal proteins L4 and L22 were amplified and sequenced. All mutants contained insertions or deletions in a protruding beta hairpin that is part of the conserved C terminus of the L22 protein and that interacts with 23S rRNA. Susceptible S. aureus RN4220 was transformed with plasmid DNA encoding the L22 alteration, resulting in transformants that were erythromycin and quinupristin resistant. Synergistic ribosomal binding of streptogramins A and B, studied by analyzing the fluorescence kinetics of pristinamycin I(A)-ribosome complexes, was abolished in the mutant strain, providing an explanation for quinupristin-dalfopristin resistance.
Subject(s)
Bacterial Proteins/genetics , Drug Resistance, Microbial/genetics , Drug Therapy, Combination/pharmacology , Mutation , RNA-Binding Proteins/genetics , Ribosomal Proteins , Staphylococcus aureus/drug effects , Virginiamycin/pharmacology , Amino Acid Sequence , Humans , Molecular Sequence Data , RNA, Ribosomal, 23S/genetics , RNA-Binding Proteins/chemistry , Ribosomes/metabolism , Staphylococcus aureus/geneticsABSTRACT
Twenty-four clinical isolates of Staphylococcus aureus collected from various geographic areas and four reference strains were studied by (i) agar diffusion with disks impregnated with 5 microg oxacillin and reading after incubation at 30C for 24 hours, (ii) Southern hybridization with a probe specific for the mecA gene, and (iii) the BBLreg CrystalTM MRSA ID system. There was perfect correlation between the three methods: the BBLreg CrystalTM MRSA ID system detected methicillin resistance in the fifteen strains hybridizing with the mecA probe and classified as resistant by the oxacillin disk diffusion test; the thirteen remaining strains were susceptible by agar diffusion and by the BBLreg test and did not hybridize with the mecA probe. The BBLreg CrystalTM MRSA ID System, therefore, appears to be an accurate method for rapid detection of Staphylococcus aureus exhibiting homogeneous resistance to methicillin.
