hmr-3647 and Respiratory-Tract-Infections

A novel series of acylides 4 were designed to overcome antibacterial resistance and evaluated for in vitro and in vivo activity. This series of acylides was designed from clarithromycin by changing the substitution on the desosamine nitrogen, followed by conversion to 3-O-acyl and 11,12-carbamate. These compounds showed significantly potent antibacterial activity against not only Gram-positive pathogens, including macrolide-lincosamide-streptogramin B (MLS(B))-resistant and efflux-resistant strains, but also Gram-negative pathogens such as Haemophilus influenzae. These acylides also showed better activity against telithromycin resistant Streptococcus pneumoniae strains.

Topics: Anti-Bacterial Agents; Chemistry, Pharmaceutical; Clarithromycin; Drug Design; Drug Resistance, Bacterial; Haemophilus influenzae; Humans; Ketolides; Microbial Sensitivity Tests; Models, Chemical; Nitrogen; Respiratory Tract Infections; Streptococcus pneumoniae

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

In an effort to find new antibiotics, a novel series of 14-membered macrolides with imidazo[4,5-b]pyridinyl sulfur contained alkyl side chains has been synthesized based on commercially available clarithromycin. Chemical transformation of hydroxy group at position C-3 afforded range of ketolides and acylides. Compared to telithromycin, compound 15a demonstrated improved in vitro activity against erythromycin-susceptible and -resistant strains.

Topics: Anti-Bacterial Agents; Chemistry, Pharmaceutical; Clarithromycin; Drug Design; Drug Resistance, Multiple, Bacterial; Erythromycin; Humans; Imidazoles; Ketolides; Macrolides; Microbial Sensitivity Tests; Models, Chemical; Respiratory Tract Infections; Staphylococcus aureus; Streptococcus pneumoniae; Sulfides; Sulfur

Respiratory tract bacterial strains are becoming increasingly resistant to currently marketed macrolide antibiotics. The current alternative telithromycin (1) from the newer ketolide class of macrolides addresses resistance but is hampered by serious safety concerns, hepatotoxicity in particular. We have discovered a novel series of azetidinyl ketolides that focus on mitigation of hepatotoxicity by minimizing hepatic turnover and time-dependent inactivation of CYP3A isoforms in the liver without compromising the potency and efficacy of 1.

Topics: Animals; Azetidines; Bacteria; Community-Acquired Infections; Disease Susceptibility; Drug Discovery; Drug Resistance, Multiple; Drug-Related Side Effects and Adverse Reactions; Humans; Ketolides; Mice; Microbial Sensitivity Tests; Respiratory Tract Infections

We investigated the in vitro activity of AR-709, a novel diaminopyrimidine antibiotic currently in development for treatment of community-acquired upper and lower respiratory tract infections, against 151 Streptococcus pneumoniae strains from various European countries. AR-709 showed excellent activity against both drug-susceptible and multidrug-resistant pneumococci.

Topics: Anti-Bacterial Agents; Community-Acquired Infections; Drug Resistance, Multiple, Bacterial; Europe; Humans; Microbial Sensitivity Tests; Pyrimidines; Respiratory Tract Infections; Streptococcus pneumoniae

We evaluated the recent prevalence of antimicrobial-resistant Haemophilus influenzae isolated from the upper respiratory tracts (URT) of patients in Japan. Mutations in the ftsI gene, which encodes penicillin binding protein 3 (PBP3), and the clonal dissemination of the resistant strains were also investigated. A total of 264 H. influenzae isolates were collected from patients with URT infections. According to the criteria of the Clinical and Laboratory Standards Institute for the susceptibility of H. influenzae to ampicillin (AMP), the isolates were distributed as follows: 161 (61.0%) susceptible strains (MIC < or = 1 microg/ml), 37 (14.0%) intermediately resistant strains (MIC = 2 microg/ml), and 66 (25.0%) resistant strains (MIC > or = 4 microg/ml). According to PCR-based genotyping, 172 (65.1%) of the isolates had mutations in the ftsI gene and were negative for the beta-lactamase (bla) gene. These 172 isolates were thus defined as genetically beta-lactamase-negative ampicillin-resistant (gBLNAR) strains. The ftsI mutant group included 98 (37.1%) strains with group I/II mutations in the variable mutated region (group I/II gBLNAR) and 74 (28.0%) strains with group III mutations in the highly mutated region (group III gBLNAR). Eighty-seven (33.0%) of the isolates were genetically beta-lactamase-negative ampicillin-susceptible (gBLNAS) strains. The group III gBLNAR strains showed resistance to beta-lactams. Only five strains (1.9%) were positive for a bla gene encoding TEM-type beta-lactamase. The three clusters consisting of 16 strains found among the 61 BLNAR strains (MIC > or = 4 microg/ml and without the bla gene) showed identical or closely related DNA restriction fragment patterns. Those isolates were frequently identified among strains with a MIC to AMP of 16 microg/ml. The current study demonstrates the apparent dissemination and spread of a resistant clone of H. influenzae among medical centers in Japan. The gBLNAR strains show a remarkable prevalence among H. influenzae isolates, with the prevalence increasing with time. This fact should be taken into account when treating URT infections.

Topics: Adolescent; Adult; Ampicillin; Ampicillin Resistance; Anti-Bacterial Agents; beta-Lactamases; Child; Child, Preschool; Female; Gene Frequency; Genotype; Haemophilus influenzae; Humans; Infant; Infant, Newborn; Japan; Male; Microbial Sensitivity Tests; Middle Aged; Mutation; Polymerase Chain Reaction; Respiratory Tract Infections

Surveillance studies conducted in the United States over the last decade have revealed increasing resistance among community-acquired respiratory pathogens, especially Streptococcus pneumoniae, that may limit future options for empirical therapy. The objective of this study was to assess the scope and magnitude of the problem at the national and regional levels during the 2005-2006 respiratory season (the season when community-acquired respiratory pathogens are prevalent) in the United States. Also, since faropenem is an oral penem being developed for the treatment of community-acquired respiratory tract infections, another study objective was to provide baseline data to benchmark changes in the susceptibility of U.S. respiratory pathogens to the drug in the future. The in vitro activities of faropenem and other agents were determined against 1,543 S. pneumoniae isolates, 978 Haemophilus influenzae isolates, and 489 Moraxella catarrhalis isolates collected from 104 U.S. laboratories across six geographic regions during the 2005-2006 respiratory season. Among S. pneumoniae isolates, the rates of resistance to penicillin, amoxicillin-clavulanate, and cefdinir were 16, 6.4, and 19.2%, respectively. The least effective agents were trimethoprim-sulfamethoxazole (SXT) and azithromycin, with resistance rates of 23.5 and 34%, respectively. Penicillin resistance rates for S. pneumoniae varied by region (from 8.7 to 22.5%), as did multidrug resistance rates for S. pneumoniae (from 8.8 to 24.9%). Resistance to beta-lactams, azithromycin, and SXT was higher among S. pneumoniae isolates from children than those from adults. beta-Lactamase production rates among H. influenzae and M. catarrhalis isolates were 27.4 and 91.6%, respectively. Faropenem MICs at which 90% of isolates are inhibited were 0.5 mug/ml for S. pneumoniae, 1 mug/ml for H. influenzae, and 0.5 mug/ml for M. catarrhalis, suggesting that faropenem shows promise as a treatment option for respiratory infections caused by contemporary resistant phenotypes.

Topics: Anti-Bacterial Agents; Azithromycin; Bacterial Infections; beta-Lactams; Community-Acquired Infections; Drug Resistance, Multiple, Bacterial; Geography; Haemophilus influenzae; Health Surveys; Humans; Moraxella catarrhalis; Penicillin Resistance; Respiratory Tract Infections; Streptococcus pneumoniae; Trimethoprim, Sulfamethoxazole Drug Combination; United States

A series of novel 6-O-arylpropargyl-9-oxime-ketolides was synthesized and evaluated against various pathogens. These new compounds show promising in vitro antibacterial potency and in vivo efficacy against macrolide resistant strains.

Topics: Animals; Anti-Bacterial Agents; Disease Models, Animal; Drug Resistance, Bacterial; Haemophilus influenzae; Ketolides; Macrolides; Rats; Respiratory Tract Infections; Staphylococcus; Structure-Activity Relationship

A novel series of erythromycin derivatives has been discovered with potent activity against key respiratory pathogens, including those resistant to erythromycin. These compounds are characterized by having an aryl group tethered to the C-6 position of the erythronolide skeleton. Extensive structural modification of the C-6 moiety led to the discovery of several promising compounds with potent activity against both mef- and erm-mediated resistant Streptoccoccus pneumoniae. Preliminary mechanistic studies indicated that the new macrolides are potent protein synthesis inhibitors, which interact with methylated ribosomes isolated from resistant organisms. In experimental animal models, these compounds exhibited excellent in vivo efficacy and balanced pharmacokinetic profiles.

Topics: Animals; Anti-Bacterial Agents; Carbamates; Cell-Free System; Drug Resistance, Multiple; Erythromycin; Haemophilus influenzae; Ketolides; Lung; Mice; Models, Molecular; Protein Biosynthesis; Protein Synthesis Inhibitors; Rats; Respiratory Tract Infections; Ribosomes; Staphylococcus aureus; Streptococcus pneumoniae; Streptococcus pyogenes; Structure-Activity Relationship; Transcription, Genetic

Topics: Animals; Anti-Bacterial Agents; Drug Design; Drug Resistance, Microbial; Haemophilus influenzae; Lung; Lung Diseases; Macrolides; Mice; Models, Molecular; Rats; Respiratory Tract Infections; Staphylococcal Infections; Staphylococcus; Streptococcal Infections; Streptococcus; Structure-Activity Relationship