Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0348321 (Haemophilus)
 15,372 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The streptogramins are a class of antibiotics remarkable for their antibacterial activity and their unique mechanism of action. These antibiotics are produced naturally, but the therapeutic use of the natural compounds is limited because they do not dissolve in water. New semisynthetic derivatives, in particular the injectable streptogramin quinupristin/dalfopristin, offer promise for treating the rising number of infections that are caused by multiply resistant bacteria. The streptogramins consist of two structurally unrelated compounds, group A and group B. The group A compounds are polyunsaturated macrolactones: the group B compounds are cyclic hexadepsipeptides. Modifications of the group B components have been mainly performed on the 3-hydroxypicolinoyl, the 4-dimethylaminophenylalanine and the 4-oxo pipecolinic residues. Semi-synthesis on this third residue led to the water-soluble derivative quinupristin. Water-soluble group A derivatives were obtained by Michael addition of aminothiols to the dehydroproline ring of pristinamycin IIA. Followed by oxidation of the intermediate sulfide into the sulfone derivatives (i.e., dalfopristin). Water-soluble derivatives (both group A and group B) can now be obtained at the industrial scale. Modified group B compounds are now also being produced by mutasynthesis, via disruption of the papA gene. Mutasynthesis has proved particularly useful for producing PIB, the group B component of the oral streptogramin RPR 106972. The streptogramins inhibit bacterial growth by disrupting the translation of mRNA into protein. Both the group A and group B compounds bind to the peptidyltransferase domain of the bacterial ribosome. The group A compounds interfere with the elongation of the polypeptide chain by preventing the binding of aa-tRNA to the ribosome and the formation of peptide bonds, while the B compounds stimulate the dissociation of the peptidyl-tRNA and may also interfere with the release of the completed polypeptide by blocking its access to the channel through which it normally leaves the ribosome. The synergy between the group A and group B compounds appears to result from an enhanced affinity of the group B compounds for the ribosome. Apparently, the group A compound induces a conformational change such that B compound binds with greater affinity. The natural streptogramins are produced as mixtures of the group A and B compounds, the combination of which is a more potent antibacterial agent than either type of compound alone. Whereas the type A or type B compound alone has, in vitro and in animal models of infection, a moderate bacteriostatic activity, the combination of the two has strong bacteriostatic activity and often bactericidal activity. Minimal inhibitory concentrations of quinupristin/dalfopristin range from 0.20 to 1 mg/l for Streptococcus pneumonae, from 0.25 to 2 mg/l for Staphylococcus aureus and from 0.50 to 4 for Enterococcus faecium, the principal target organisms of this drug. Quinupristin/dalfopristin also has activity against mycoplasmas, Neisseria gonorrhoeae, Haemophilus influenz, Legionella spp. and Moraxella catarrhalis. Bacteria develop resistance to the streptogramms by ribosomal modification, by producing inactivating enzymes, or by causing an efflux of the antibiotic. Dimethylation of an adenine residue in rRNA, a reaction that is catalyzed by a methylase encoded by the erm gene class, affects the binding of group B compounds (as well as the macrolides and lincosamides; hence, MLSB resistance), but group A and B compounds usually maintain their synergy and their bactericidal effect against MLSB-resistant strains. erm genes are widespread both geographically and throughout numerous bacterial genera. Several types of enzymes (acetyltransferases, hydrolases) have been identified that inactivate the group A or the group B compounds. Genes involved in streptogramin efflux have so far been found only in staphylococci, particularly in coagulase-negative species
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PMID:Recent developments in streptogramin research. 1019 38

Macrolide antibiotics (Mac) consist of a 12- to 16-membered lactone ring combined with a sugar moiety, and they inhibit protein synthesis via binding to 23S ribosomal RNA in bacteria. The 14- and 16-membered Mac are used for treating infectious diseases caused by Gram-positive and other bacteria; e.g., Haemophilus influenzae, Bordetella pertussis, Legionella pneumophila, Campylobacter, Treponema pallidum and Mycoplasma. Resistance to macrolide, lincosamide, and streptogramin-B (MLS) antibiotics in staphylococci is known to have the following mechanisms: 1) alteration of the target on ribosome due to dimethylation of a specific adenine residue in the 23S ribosomal RNA by the product of the erm gene, and consequently a decrease in binding of MLS antibiotics; 2) inactivation of streptogramin-B (STG-B) and lincosamide by the products of the sbh (encoding streptogramin B hydrolase) and linA' (encoding 3-lincomycin 4-clindamycin O-nucleotidyltransferase) genes, respectively; and 3) active efflux of Mac and STG-B antibiotics determined by the msrA and msrB genes in Staphylococcus epidermidis and Staphylococcus xylosus, respectively, both of which appear to act as an ATP-dependent efflux pump. I have shown that Staphylococcus aureus 8325(pEP2104) exhibits inducible resistance to PMS (partial macrolide and streptogramin B)-antibiotics [the 14-membered macrolides, erythromycin (EM), and oleandomycin (OL), and the 16-membered macrolide mycinamicin (MCM) and STG-B]. The sequence of the N-terminal amino acid residues of a 63 kDa protein (MsrSA) that appeared in the membrane of PMS-resistant strains was identical to that of an MsrA polypeptide related to enhanced efflux of [14C]EM. Ribosomes from PMS-resistant strains showed a similar affinity for EM to those from the PMS-sensitive host strain NCTC8325, and no inactivation of EM by 8325(pEP2104) was observed. In the present study, I showed the DNA sequence of the msrSA region on the constitutive PMS-resistant plasmid pMC38, PMS-inducible resistant plasmid pEP2104 and PMS-sensitive mutant plasmid pSP6, and the region that is essential for inducible expression in PMS resistance. In addition, I investigated the relationship between PMS resistance and intracellular accumulation of EM.
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PMID:[Study of macrolide, lincosamide, and streptogramin B antibiotics resistance in Staphylococcus aureus]. 1077 59

Telithromycin, the first of the ketolide antimicrobials, has been specifically designed to provide potent activity against common and atypical/intracellular or cell-associated respiratory pathogens, including those that are resistant to beta-lactams and/or macrolide-lincosamide-streptograminB (MLS(B)) antimicrobials. Against gram-positive cocci, telithromycin possesses more potent activity in vitro and in vivo than the macrolides clarithromycin and azithromycin. It retains its activity against erm-(MLS(B)) or mef-mediated macrolide-resistant Streptococcus pneumoniae and Streptococcus pyogenes and against Staphylococcus aureus resistant to macrolides through inducible MLS(B) mechanisms. Telithromycin also possesses high activity against the Gram-negative pathogens Haemophilus influenzae and Moraxella catarrhalis, regardless of beta-lactamase production. In vitro, it shows similar activity to azithromycin against H. influenzae, while in vivo its activity against H. influenzae is higher than that of azithromycin. Telithromycin's spectrum of activity also extends to the atypical, intracellular and cell-associated pathogens Legionella pneumophila, Mycoplasma pneumoniae and Chlamydia pneumoniae. In vitro, telithromycin does not induce MLS(B) resistance and it shows low potential to select for resistance or cross-resistance to other antimicrobials. These characteristics indicate that telithromycin will have an important clinical role in the empirical treatment of community-acquired respiratory tract infections.
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PMID:Microbiological profile of telithromycin, the first ketolide antimicrobial. 1152 58

Antimicrobial resistance amongst common respiratory pathogens has increased worldwide at an alarming rate and now threatens the clinical usefulness of a number of antibacterial agents. A major concern is the selection of resistance in the community, which tends to parallel the (often inappropriate) overuse of such agents. Such problems highlight the need for new antibacterial agents that retain activity against bacterial strains resistant to existing agents, and have a low potential to select for resistance or induce cross-resistance. Telithromycin is the first of a new family of antibacterials--the ketolides--and has been designed specifically for the treatment of community-acquired respiratory tract infections (RTIs). Numerous in vitro studies confirm the potent activity of telithromycin against pathogens commonly implicated in community-acquired RTIs, irrespective of their beta-lactam, macrolide or fluoroquinolone susceptibility. Against pneumococci, for example, MICs were < or = 1 mg/L irrespective of penicillin susceptibility, with > or = 98% of macrolide-resistant strains inhibited at < or = 0.5 mg/L, regardless of the underlying mechanism of resistance (including erm, mef and ribosomal L4 mutations). Against Haemophilus influenzae and Moraxella catarrhalis, including beta-lactamase-positive strains, telithromycin is at least as potent as azithromycin. In addition, telithromycin has a very low potential for selection of resistant isolates or induction of cross-resistance. Importantly, and unlike existing macrolides, telithromycin does not induce MLS(B) resistance, a finding explained by the presence of the innovative 3-keto group in its chemical structure. Telithromycin therefore represents an important addition to the therapeutic armamentarium in an era of increasing antimicrobial resistance, with an expected low likelihood of the development of resistance in clinical use.
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PMID:Overcoming antimicrobial resistance: profile of a new ketolide antibacterial, telithromycin. 1156 72

PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) is a global surveillance study established in 1999 to monitor antibacterial resistance of respiratory tract organisms. Thirteen centers from Argentina, Brazil and Mexico participated during 1999-2000; they collected 1806 isolates (Streptococcus pneumoniae 518, Haemophilus influenzae 520, Moraxella catarrhalis 140, Staphylococcus aureus 351, S. pyogenes 277). Overall, 218 (42.1%) of the S. pneumoniae isolates had reduced susceptibility to penicillin, 79 (15.3%) were penicillin-resistant and 79 (15.3%) were erythromycin-resistant. Mexico had the highest prevalence of penicillin (76.5%) and erythromycin (31.2%) resistance. Of 77 erythromycin-resistant S. pneumoniae tested for resistance genotype, 43 possessed mef(A), 33 possessed erm(B) and 1 possessed both erm(B) and mef(A) mechanism. All S. pneumoniae isolates were fully susceptible to telithromycin, linezolid, teicoplanin and vancomycin. Among H. influenzae isolates, 88 (16.9%) produced beta-lactamase, ranging from 11% (Brazil) to 24.5% (Mexico). Among M. catarrhalis isolates, 138 (98.6%) produced beta-lactamase. Twenty-four (8.7%) of the S. pyogenes isolates were erythromycin-resistant; resistance being attributable to mefA (n=18), ermTR (n=5) and ermB (n=1). All H. influenzae, M. catarrhalis and S. pyogenes were fully susceptible to telithromycin. Methicillin resistance was found in 26.5% of the S. aureus isolates (Argentina 15%; Mexico 20%; Brazil 31.3%). Telithromycin was effective against 97.7% of methicillin-susceptible isolates. PROTEKT confirms that antibacterial resistance is an emerging problem in Latin America. The previously reported high levels of pneumococcal resistance to the beta-lactam and macrolides were exceeded. New agents that do not induce resistance or that exert low selective pressure, e.g. telithromycin, are essential to safeguard future antibacterial efficacy.
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PMID:Antibacterial resistance of community-acquired respiratory tract pathogens recovered from patients in Latin America: results from the PROTEKT surveillance study (1999-2000). 1280 91

Resistance to commonly used antimicrobial agents among the key respiratory pathogens is increasing worldwide and therefore a rational choice of an empirical treatment requires knowledge of both global and local resistance patterns. The susceptibility of 185 Streptococcus pneumoniae and 169 Haemophilus influenzae isolates collected from January 1999 to May 2002 at the Children's Memorial Health Institute, Warsaw, Poland, from 351 children with community-acquired respiratory tract infections (RTIs) has been determined. Of S. pneumoniae isolates, 84% were susceptible to penicillin, 91% to cefaclor, 95% to cefuroxime, 98% to cefotaxime, 79% to erythromycin, 46% to co-trimoxazole, 82% to clindamycin and 59% to tetracycline. The majority (83%) of erythromycin-resistant isolates tested carried the erm(B) gene, conferring the MLS(B) phenotype. All tetracycline-resistant S. pneumoniae strains analysed were tet(M) positive and tet(O) negative. A total of 24% of H. influenzae isolates were beta-lactamase-positive. H. influenzae susceptibility to amoxicillin/clavulanate, cefaclor, cefuroxime, azithromycin, tetracycline and co-trimoxazole was 100, 89, 94, 96, 96 and 43%, respectively.
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PMID:Antimicrobial resistance of Streptococcus pneumoniae and Haemophilus influenzae isolated from children with community-acquired respiratory tract infections in Central Poland. 1473 12

In vitro activities of erythromycin A, telithromycin, and two investigational ketolides, JNJ-17155437 and JNJ-17155528, were evaluated against clinical bacterial strains, including selected common respiratory tract pathogens. Against 46 macrolide-susceptible and -resistant Streptococcus pneumoniae strains, the MIC(90) (MIC at which 90% of the isolates tested were inhibited) of the investigational ketolides was 0.25 microg/ml, twofold lower than that of telithromycin and at least 64-fold lower than that of erythromycin A. Against erm(B)-containing pneumococci, the MIC(90) of all the ketolides was 0.06 microg/ml. The MIC(90) of the investigational ketolides against mef(A)-containing pneumococci or pneumococci with both mef(A) and erm(B) was 0.25 microg/ml, two-and fourfold lower, respectively, than that of telithromycin. In contrast, the MICs of the investigational ketolides against macrolide-resistant S. pneumoniae strains with ribosomal mutations were similar to or, in some cases, as much as eightfold higher than those of telithromycin. Against Haemophilus influenzae, MICs of all the ketolides were < or =2 microg/ml. Against three Moraxella catarrhalis isolates, the MIC of the ketolides was 0.25 microg/ml. The ketolides inhibited in vitro protein synthesis, with 50% inhibitory concentrations ranging from 0.23 to 0.27 microM. In time-kill studies against macrolide-susceptible and erm- or mef-containing pneumococci, the ketolides were bacteriostatic to slowly bactericidal, with 24-h log(10) decreases ranging from 2.0 to 4.1 CFU. Intervals of postantibiotic effects for the ketolides against macrolide-susceptible and -resistant S. pneumoniae were 3.0 to 8.1 h.
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PMID:In vitro activities of novel 2-fluoro-naphthyridine-containing ketolides. 1561 10

Novel C6-carbamate ketolides with C2-fluorination and C9-oximation have been synthesized. The best compounds in this series displayed MIC values of 0.03-0.12 microg/mL against streptococci containing erm and mef resistance determinants and 2-4 microg/mL against Haemophilus influenzae. Several compounds also showed measurable activity against erm(B)-containing enterococci with MIC values of 2-8 microg/mL. In vivo activity was adversely affected by fluorination, possibly as a result of increased serum protein binding.
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PMID:Synthesis and antibacterial activity of C2-fluoro, C6-carbamate ketolides, and their C9-oximes. 1568 80

Antimicrobial resistance is a growing problem among upper respiratory tract pathogens. Resistance to beta-lactam drugs among Streptococcus pneumoniae, Haemophilus influenzae, and Streptococcus pyogenes is increasing. As safe and well-tolerated antibiotics, macrolides play a key role in the treatment of community-acquired upper respiratory tract infections (RTIs). Their broad spectrum of activity against gram-positive cocci, such as S. pneumoniae and S. pyogenes, atypical pathogens, H. influenzae (azithromycin and clarithromycin), and Moraxella catarrhalis, has led to the widespread use of macrolides for empiric treatment of upper RTIs and as alternatives for patients allergic to b-lactams. Macrolide resistance is increasing among pneumococci and recently among S. pyogenes, and is associated with increasing use of the newer macrolides, such as azithromycin. Ribosomal target modification mediated by erm(A) and erm(B) genes and active efflux due to mef(A) and mef(E) are the principal mechanisms of resistance in S. pneumoniae and S. pyogenes. Recently, ribosomal protein and RNA mutations have been found responsible for acquired resistance to macrolides in S. pneumoniae, S. pyogenes, and H. influenzae. Although macrolides are only weakly active against macrolide-resistant streptococci species producing an efflux pump (mef) and are inactive against pathogens with ribosomal target modification (erm), treatment failures are uncommon. Therefore, macrolide therapy, for now, remains a good alternative for treatment of upper RTIs; however, continuous monitoring of the local resistance patterns is essential.
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PMID:The Use of Macrolides in Treatment of Upper Respiratory Tract Infections. 1584 19

Data are presented on antimicrobial resistance among isolates of Streptococcus pneumoniae, Streptoco-ccus pyogenes, Haemophilus influenzae, and Moraxella catarrhalis collected in Japan during years 1-3 (1999-2002) of the Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin (PROTEKT) surveillance study. In addition to the standard panel of PROTEKT antimicrobial agents, eight other agents often used in Japan also were tested against these isolates. The majority (30%-55%) of S. pneumoniae and H. influenzae isolates were collected from patients with community-acquired pneumonia, whereas most (>70%) S. pyogenes isolates came from patients with tonsillitis/pharyngitis. Penicillin and macrolide resistance were high among isolates of S. pneumoniae, averaging 30.9%-44.5% and 77.2%-79.9%, respectively, across all centers over the 3 study years; the highest occurrences were reported among pediatric patients aged 0-2 years. The erm(B) genotype accounted for >50% of all erythromycin-resistant isolates each study year. S. pyogenes isolates were highly susceptible to most antimicrobial agents except the macrolides and tetracycline. beta-Lactamase production among H. influenzae isolates range was 8.5%-9.7% per annum. A total of 9 beta-lactamase-negative, ampicillin-resistant isolates were collected during the study. Almost all (>95%) M. catarrhalis isolates were beta-lactamase positive each year. Telithromycin was highly active against all pathogens examined in this study during all 3 years.
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PMID:Antimicrobial susceptibility of respiratory tract pathogens in Japan during PROTEKT years 1-3 (1999-2002). 1650 84


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