No abstract

A variety of 1β-methylcarbapenem derivatives were screened to identify inhibitors of IMP-1 metallo-β-lactamase, a class B β-lactamase, in an automated microassay system using nitrocefin as a substrate. The structure–inhibitory-activity relationship study revealed that three types of 1β-methylcarbapenems having benzothienylthio, dithiocarbamate, or pyrrolidinylthio moieties at the C-2 position showed good inhibitory activity. Among the compounds screened, J-110,441, having a benzothienylthio moiety at the C-2 position of 1β-methylcarbapenem, was the most potent inhibitor of class B metallo-β-lactamases with Ki values of 0.0037, 0.23, 1.00, and 0.83 μM for IMP-1 encoded by thebla IMP gene, CcrA from Bacteroides fragilis, L1 from Stenotrophomonas maltophilia, and type II from Bacillus cereus, respectively. In a further characterization study, J-110,441 also showed inhibitory activity against TEM-type class A serine β-lactamase and chromosomal class C serine β-lactamase from Enterobacter cloacae withKi values of 2.54 and 0.037 μM, respectively. Combining imipenem or ceftazidime with J-110,441 had a synergistic effect on the antimicrobial activity against β-lactamase-producing bacteria. Against the isolates of IMP-1-producing Serratia marcescens, the MICs of imipenem decreased to levels ranging from 1/64 to 1/4 in the presence of one-fourth of the MIC of J-110,441. Against E. cloacae producing high levels of class C β-lactamase, the MIC of ceftazidime decreased from 64 to 4 μg/ml in the presence of 4 μg of J-110,441 per ml. This is the first report to describe a new class of inhibitor of class B and class C β-lactamases including transferable IMP-1 metallo-β-lactamases.

No abstract

No abstract

We report the first case of familial C3 glomerulonephritis (C3GN) associated with mutations in the gene for complement factor B (CFB). A 12-year-old girl was diagnosed with biopsy-proven C3GN. Her mother had a history of treatment for membranoproliferative glomerulonephritis, and her brother had hypocomplementemia without urinary abnormalities. DNA analysis revealed heterozygosity for CFB p.S367R in the patient, mother and brother. Evaluation of the structure-function relationship supports that this mutation has gain-of-function effects in CFB. The present case suggests that CFB has an important role in the etiology of C3GN and provides a new insight into anticomplement therapy approaches.