Abstract:
:Artermisinin and its derivatives are now the mainstays of antimalarial treatment; however, their mechanism of action is only poorly understood. We report on the synthesis of a novel series of epoxy-endoperoxides that can be prepared in high yields from simple starting materials. Endoperoxides that are disubstituted with alkyl or benzyl side chains show efficient inhibition of the growth of both chloroquine-sensitive and -resistant strains of Plasmodium falciparum. A trans-epoxide with respect to the peroxide linkage increases the activity compared to that of its cis-epoxy counterpart or the parent endoperoxide. The novel endoperoxides do not show a strong interaction with artemisinin. We have compared the mechanism of action of the novel endoperoxides with that of artemisinin. Electron microscopy reveals that the novel endoperoxides cause the early accumulation of endocytic vesicles, while artemisinin causes the disruption of the digestive vacuole membrane. At longer incubation times artemisinin causes extensive loss of organellar structures, while the novel endoperoxides cause myelin body formation as well as the accumulation of endocytic vesicles. An early event following endoperoxide treatment is the redistribution of the pH-sensitive probe LysoSensor Blue from the digestive vacuole to punctate structures. By contrast, neither artemisinin nor the novel endoperoxides caused alterations in the morphology of the endoplasmic reticulum nor showed antagonistic antimalarial activity when they were used with thapsigargin. Analysis of rhodamine 123 uptake by P. falciparum suggests that disruption of the mitochondrial membrane potential occurs as a downstream effect rather than as an initiator of parasite killing. The data suggest that the digestive vacuole is an important initial site of endoperoxide antimalarial activity.
journal_name
Antimicrob Agents Chemotherjournal_title
Antimicrobial agents and chemotherapyauthors
del Pilar Crespo M,Avery TD,Hanssen E,Fox E,Robinson TV,Valente P,Taylor DK,Tilley Ldoi
10.1128/AAC.00609-07subject
Has Abstractpub_date
2008-01-01 00:00:00pages
98-109issue
1eissn
0066-4804issn
1098-6596pii
AAC.00609-07journal_volume
52pub_type
杂志文章abstract::The in vitro activities of two new carboxyquinolones, A-56619 (difloxacin) and A-56620, were compared with those of ciprofloxacin, norfloxacin, and ofloxacin against genital tract pathogens. All the quinolones were highly active against Neisseria gonorrhoeae. A-56619 had the lowest MICs against Chlamydia trachomatis (...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.30.6.948
更新日期:1986-12-01 00:00:00
abstract::The activity of clavulanic acid alone and in combination with penicillin, amoxycillin, and carbenicillin was studied. Marked reductions in the minimum inhibitory concentrations (MICs) for a wide spectrum of beta-lactamase-producing clinical isolates were found. Of particular interest were the decreased MICs of penicil...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.13.3.389
更新日期:1978-03-01 00:00:00
abstract::Induction of the cloned ampC Citrobacter freundii beta-lactamase in Escherichia coli by 6-aminopenicillanic acid was prevented by periplasmic TEM beta-lactamase in the same cell. In contrast, cytoplasmic TEM beta-lactamase did not prevent induction. This result implies that entry of the beta-lactam into the cytoplasm ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.34.12.2429
更新日期:1990-12-01 00:00:00
abstract::Resistance to 5-fluorocytosine was studied in 137 independent Candida albicans clinical isolates. Seventy-eight isolates (57%) were susceptible; 51 isolates (37%) were partially resistant; 8 isolates (6%) were highly resistant. All partially resistant isolates gave rise to variants which were highly resistant. Some su...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.22.5.810
更新日期:1982-11-01 00:00:00
abstract::5-episisomicin (Sch 22591) is a novel semisynthetic aminoglycoside with a spectrum and potency similar to gentamicin in its activity against susceptible bacterial strains, but with increased potency against Pseudomonas, Providencia, and Proteus rettgeri. It is also more active than tobramycin and amikacin against thes...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.13.1.41
更新日期:1978-01-01 00:00:00
abstract::The efficacy of ticarcillin-clavulanic acid was compared with the efficacies of standard antistaphylococcal agents (flucloxacillin, oxacillin, nafcillin, and vancomycin) and ticarcillin in an experimental model of Staphylococcus aureus endocarditis. Therapy was either initiated soon (8 h) after infection, when numbers...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.36.2.458
更新日期:1992-02-01 00:00:00
abstract::Wild-type Proteus strains are usually resistant to colistin. We have observed an increase in the level of colistin resistance in four clinical isolates of P. vulgaris, P. morganii, and P. rettgeri by prior treatment with subinhibitory concentrations of the drug. The enhanced resistance in these strains was lost after ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.12.1.1
更新日期:1977-07-01 00:00:00
abstract::Six tetraoxanes had 50% inhibitory concentrations in the range of 10 to 100 ng/ml against Plasmodium falciparum, whereas the corresponding hexaoxonanes had minimal antimalarial activity. The lack of iron-mediated reactivity of the hexaoxonanes may explain their low activity compared to the tetraoxanes, the latter of w...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00264-07
更新日期:2007-08-01 00:00:00
abstract::Rifalazil, also known as KRM-1648 or benzoxazinorifamycin, is a new semisynthetic rifamycin with a long half-life of approximately 60 h. Rifalazil has potent bactericidal activity against Mycobacterium tuberculosis in vitro and in animal models of tuberculosis (TB). Prior studies in healthy volunteers showed that once...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1128/AAC.45.7.1972-1976.2001
更新日期:2001-07-01 00:00:00
abstract::The pharmacokinetics of gentamicin in 34 febrile neutropenic patients (40 courses) were compared with those in 40 nonneutropenic patients receiving the drug. No pharmacokinetic differences were seen in half-life, volume of distribution (liter per kilogram; total and ideal body weight), or clearance (milliliter per min...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.33.11.1890
更新日期:1989-11-01 00:00:00
abstract::Topical administration of live commensal bacteria to the vaginal tract holds significant potential as a cost-effective strategy for the treatment of sexually transmitted infections and the delivery of mucosal vaccines. Probiotic-releasing intravaginal rings (IVRs) embody significant theoretical advantages over traditi...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02542-13
更新日期:2014-01-01 00:00:00
abstract::A fluorometric assay, based on the natural fluorescence of the quinolone nucleus, was used to determine the uptake of ofloxacin by human polymorphonuclear leukocytes. The ratio of cellular concentration to extracellular concentration (C/E) at 20 min and 37 degrees C was 7.2, using an extracellular concentration of 5 m...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.33.5.653
更新日期:1989-05-01 00:00:00
abstract::Detection of bacterial growth by measuring the release of (14)CO(2) from the metabolism of uniformly labeled (14)C-glucose has proven to be accurate, sensitive, and rapid. The inhibition of glucose metabolism by antibiotics as an index of bacterial susceptibility was evaluated based on radiometric methodology. Bacteri...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.2.5.405
更新日期:1972-11-01 00:00:00
abstract::Ten (0.05%) of 18,628 strains of Streptococcus pyogenes isolated from clinical specimens in the 3 years 1968 to 1970 were resistant to lincomycin and erythromycin. All 10 strains were highly resistant to lincomycin, having minimal inhibitory concentration (MIC) values of 200 mug/ml. There were two degrees of resistanc...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.1.4.333
更新日期:1972-04-01 00:00:00
abstract::Twenty strains of Staphylococcus aureus isolated from patients with endocarditis were examined in vitro for susceptibility to rifampin, nafcillin, and vancomycin and to combinations of rifampin with nafcillin or vancomycin. Minimum bactericidal concentrations of rifampin ranged from 0.0031 to 0.0125 mug/ml, of nafcill...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.13.5.759
更新日期:1978-05-01 00:00:00
abstract::The in vivo efficacy of ciprofloxacin or pefloxacin alone or in combination with fosfomycin was evaluated in experimental aortic valve endocarditis induced in 133 rabbits by a multidrug-susceptible or multidrug-resistant strain of Pseudomonas aeruginosa. Therapy was initiated early (12 h after infection), when bacteri...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.39.2.496
更新日期:1995-02-01 00:00:00
abstract::One way to speed up the TB drug discovery process is to search for antitubercular activity among compound series that already possess some of the key properties needed in anti-infective drug discovery, such as whole-cell activity and oral absorption. Here, we present MGIs, a new series of Mycobacterium tuberculosis gy...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.03913-14
更新日期:2015-04-01 00:00:00
abstract::Eighteen patients developed abnormally low serum glutamic oxaloacetic transaminase values during metronidazole therapy. Metronidazole absorbs at 340 nm, simulating reduced nicotinamide adenine dinucleotide, which is the final colorimetric product of the serum glutamic oxaloacetic transaminase assay. ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.14.4.636
更新日期:1978-10-01 00:00:00
abstract::We determined the antibiotic susceptibilities of 1,785 enterococcal bloodstream isolates collected over 25 years. Antibiotic resistance emerged at a greater rate in Enterococcus faecium than in other enterococcal species, and E. faecium isolates became proportionally more common over time. Our findings confirm the pat...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.46.11.3676-3678.2002
更新日期:2002-11-01 00:00:00
abstract::Streptococcus pneumoniae, a major cause of human disease, produces a 17-mer autoinducer peptide pheromone (competence-stimulating peptide [CSP]) for the control of competence for genetic transformation. Due to previous work linking CSP to stress phenotypes, we set up an in vivo sepsis model to assay its effect on viru...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.48.12.4725-4732.2004
更新日期:2004-12-01 00:00:00
abstract::To investigate whether grapefruit juice inhibits the metabolism of clarithromycin, 12 healthy subjects were given water or grapefruit juice before and after a clarithromycin dose of 500 mg in a randomized crossover study. Administration of grapefruit juice increased the time to peak concentration of both clarithromyci...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1128/AAC.42.4.927
更新日期:1998-04-01 00:00:00
abstract::Twenty-one adult patients hospitalized with lower respiratory tract infections due to Branhamella catarrhalis or Haemophilus influenzae or both were treated with the combination of oral amoxicillin and potassium clavulanate (Augmentin) in an open, noncomparative clinical trial. Diseases included pneumonia, empyema, an...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.27.6.912
更新日期:1985-06-01 00:00:00
abstract::Mycobacterium tuberculosis, the causative agent of human tuberculosis (TB), has surpassed HIV/AIDS as the leading cause of death from a single infectious agent. The increasing occurrence of drug-resistant strains has become a major challenge for health care systems and, in some cases, has rendered TB untreatable. Howe...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01846-18
更新日期:2019-01-29 00:00:00
abstract::Mycobacterium smegmatis DSM43756 inactivates rifampin, and the inactivated antibiotic product recovered from culture medium was ribosylated on the 23-OH group. To study this process, the gene responsible for the inactivation was expressed at high levels by the lac promoter in Escherichia coli conferring resistance to ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.43.1.181
更新日期:1999-01-01 00:00:00
abstract::There is a high prevalence of beta-lactam- and macrolide-resistant Streptococcus pneumoniae in Taiwan. To understand the in vitro susceptibilities of recent isolates of S. pneumoniae to fluoroquinolones and telithromycin (which is not available in Taiwan), the MICs of 23 antimicrobial agents for 936 clinical isolates ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章,多中心研究
doi:10.1128/aac.47.7.2145-2151.2003
更新日期:2003-07-01 00:00:00
abstract::The goal of the present study was to examine the ability of cytochrome P450-2C9 (CYP2C9) to activate cyclophosphamide (CPA) and elicit tumor cell death. A CYP2C9-deficient human lymphoblastoid cell line (AHH-1 cells) and a derivative cell line (H2C9 cells) stably transfected with a cDNA encoding CYP2C9 were used. The ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.44.10.2659-2663.2000
更新日期:2000-10-01 00:00:00
abstract::The in vitro activity of gentamicin was compared with its therapeutic efficacy in rabbits with Streptococcus faecalis endocarditis. The test strain was resistant to gentamicin as measured by MICs and MBCs determined in Mueller-Hinton broth alone or in broth supplemented with 50% rabbit serum. Gentamicin also failed to...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.27.2.224
更新日期:1985-02-01 00:00:00
abstract::After inducing mutagenesis with nitrosoguanidine, we used vancomycin enrichment in isolating auxotrophic mutants of Mycobacterium smegmatis. Compared with cycloserine and penicillin G, which are also cell wall inhibitors, vancomycin, with 24 h of exposure, produced less cell lysis and a greater reduction in viable cel...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.19.4.571
更新日期:1981-04-01 00:00:00
abstract::The report describes the establishment and characterization of a mouse xenograft transplantation model for the study of papillomavirus infection of bovine skin. Calf scrotal skin was inoculated with bovine papillomavirus type 2 before grafting it to the dorsum of severe combined immunodeficient mice. The grafted skin ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.45.4.1014-1021.2001
更新日期:2001-04-01 00:00:00
abstract::Seventy-five strains of Haemophilus influenzae type b, including 45 beta-lactamase-positive strains, were tested by MIC and time kill studies for susceptibility to ampicillin-sulbactam at various ratios. beta-Lactamase-negative strains were inhibited by lower concentrations of ampicillin-sulbactam than beta-lactamase-...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.33.9.1620
更新日期:1989-09-01 00:00:00