hmr-3647 and Pneumococcal-Infections

Macrolide antibiotics are widely prescribed for the treatment of respiratory tract infections; however, the increasing prevalence of macrolide-resistant pathogens is a public health concern. Therefore, the development of new macrolide scaffolds with activities against resistant pathogens is urgently needed. An efficient method for reconstructing the erythromycin A macrolactone skeleton has been established. Based on this methodology, novel 15-membered macrolides, known as '11a-azalides', with substituents at the C12, C13, or C4″ positions were synthesized and their antibacterial activities were evaluated. These derivatives showed promising antibacterial activities against erythromycin-resistant Streptococcus pneumoniae. Among them, the C4″ substituted derivatives had the most potent activity against erythromycin-resistant S. pneumoniae.

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Erythromycin; Humans; Macrolides; Pneumococcal Infections; Respiratory Tract Infections; Streptococcus pneumoniae; Structure-Activity Relationship

Synthesis, antibacterial activity and pharmacokinetic properties of a novel class of macrolide antibiotics-macrolones-derived from azithromycin, comprising oxygen atom(s) in the linker and either free or esterified quinolone 3-carboxylic group, are reported. Selected compounds showed excellent antibacterial potency towards key erythromycin resistant respiratory pathogens. However, the majority of compounds lacked good bioavailability. The isopropyl ester, compound 35, and a macrolone derivative with an elongated linker 29 showed the best oral bioavailability in rats, both accompanied with an excellent overall microbiology profile addressing inducible and constitutive MLSb as well as efflux mediated macrolide resistance in streptococci, while compound 29 is more potent against staphylococci.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Azithromycin; Biological Availability; Carboxylic Acids; Crystallography, X-Ray; Drug Stability; Esters; Humans; Injections, Intravenous; Macrolides; Male; Microbial Sensitivity Tests; Microsomes, Liver; Models, Molecular; Pneumococcal Infections; Rats; Rats, Wistar; Streptococcus pneumoniae

Of 393 isolates of Streptococcus pneumoniae from U.S. children collected in 2005-2006, nonvaccine serotypes accounted for 89.1%, with serotype 19A the most prevalent, representing 30.5% of all isolates. The MIC(90) of faropenem against serotype 19A isolates was 1 mug/ml, compared to > or =8 microg/ml against amoxicillin/clavulanate, cefdinir, cefuroxime axetil, and azithromycin.

Topics: Adolescent; Anti-Bacterial Agents; beta-Lactams; Child; Child, Preschool; Drug Resistance, Bacterial; Humans; Infant; Microbial Sensitivity Tests; Phenotype; Pneumococcal Infections; Serotyping; Streptococcus pneumoniae; United States

A rare clinical isolate of Streptococcus pneumoniae, highly resistant to telithromycin, contained erm(B) with a truncated leader peptide and a mutant ribosomal protein L4. By transformation of susceptible strains, this study shows that high-level telithromycin resistance is conferred by erm(B), wild type or mutant, in combination with a (69)GTG(71)-to-TPS mutation in ribosomal protein L4.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Culture Media; Drug Resistance, Bacterial; Genotype; Humans; Ketolides; Methyltransferases; Microbial Sensitivity Tests; Mutation; Phenotype; Pneumococcal Infections; Ribosomal Proteins; Streptococcus pneumoniae

Isolates (3,845) obtained from German adults with invasive pneumococcal disease between 1992 and 2004 were investigated. Of these, 430 isolates (11.2%) were erythromycin A nonsusceptible. Macrolide resistance genotypes and multilocus sequence types were determined. Among the isolates, 35.6% were erm(B) positive and 63.5% were mef positive. Over the study period, the frequency of resistance rose significantly from 2.2 to 17.0% (P < 0.001). A serotype 14, sequence type 9 clone was the most widespread.

Topics: Adult; Anti-Bacterial Agents; Bacterial Proteins; Drug Resistance, Bacterial; Erythromycin; Humans; Macrolides; Membrane Proteins; Pneumococcal Infections; Sequence Analysis, DNA; Streptococcus pneumoniae

The aim of this study was to analyze the distributions of antibiotic susceptibility patterns, serotypes, phenotypes, genotypes, and macrolide resistance genes among 125 nonduplicated erythromycin-resistant Streptococcus pneumoniae clinical isolates collected in a Spanish point prevalence study. The prevalence of resistance to macrolides in this study was 34.7%. Multiresistance (to three or more antimicrobials) was observed in 81.6% of these strains. Among 15 antimicrobials studied, cefotaxime, moxifloxacin, telithromycin, and quinupristin-dalfopristin were the most active drugs. The most frequent serotypes of erythromycin-resistant isolates were 19F (25%), 19A (17%), 6B (12%), 14 (10%), and 23F (10%). Of the 125 strains, 109 (87.2%) showed the MLS(B) phenotype [103 had the erm(B) gene and 6 had both erm(B) and mef(E) genes]. Sixteen (12.8%) strains showed the M phenotype [14 with mef(E) and 2 with mef(A)]. All isolates were tested by PCR for the presence of the int, xis, tnpR, and tnpA genes associated with conjugative transposons (Tn916 family and Tn917). Positive detection of erm(B), tet(M), int, and xis genes related to the Tn916 family was found in 77.1% of MLS(B) phenotype strains. In 16 strains, only the tndX, erm(B), and tet(M) genes were detected, suggesting the presence of Tn1116, a transposon recently described for Streptococcus pyogenes. Five clones, namely, Sweden(15A)-25, clone(19F) ST87, Spain(23F)-1, Spain(6B)-2, and clone(19A) ST276, accounted for half of the MLS(B) strains. In conclusion, the majority of erythromycin-resistant pneumococci isolated in Spain had the MLS(B) phenotype, belonged to multiresistant international clones, and carried the erm(B), tet(M), xis, and int genes, suggesting the spread of transposons of the Tn916 family.

Topics: Anti-Bacterial Agents; Clone Cells; Drug Resistance, Multiple, Bacterial; Electrophoresis, Polyacrylamide Gel; Erythromycin; Genes, Bacterial; Microbial Sensitivity Tests; Phenotype; Pneumococcal Infections; Serotyping; Spain; Streptococcus pneumoniae; Tetracycline Resistance

A novel series of C12 vinyl erythromycin derivatives have been discovered which exhibit in vitro and in vivo potency against key respiratory pathogens. The C12 modification involves replacing the natural C12 methyl group in the erythromycin core with a vinyl group via chemical synthesis. From the C12 vinyl macrolide core, a series of C12 vinyl ketolides was prepared. Several compounds were found to be potent against macrolide-sensitive and -resistant bacteria. The C12 vinyl ketolides 6j and 6k showed a similar antimicrobial spectrum and comparable activity to the commercial ketolide telithromycin. However, the pharmacokinetic profiles of C12 vinyl ketolides 6j and 6k in rats differ from that of telithromycin by having higher lung-to-plasma ratios, larger volumes of distribution, and longer half-lives. These pharmacokinetic differences have a pharmacodynamic effect as both 6j and 6k exhibited better in vivo efficacy than telithromycin in rat lung infection models against Streptococcus pneumoniae and Haemophilus influenzae.

Topics: Animals; Anti-Bacterial Agents; Biological Availability; Drug Resistance, Bacterial; Enterococcus faecalis; Haemophilus Infections; Haemophilus influenzae; Half-Life; Ketolides; Lung Diseases; Male; Microbial Sensitivity Tests; Pneumococcal Infections; Rats; Rats, Sprague-Dawley; Staphylococcus aureus; Streptococcus pneumoniae; Streptococcus pyogenes; Structure-Activity Relationship; Vinyl Compounds